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The Many Ways to Myocardial Perfusion Imaging

Posted on: Sunday, 12 June 2005, 03:00 CDT

Myocardial perfusion imaging (MPI) is important for the management of patients with suspected or known coronary artery disease (CAD). Nuclear cardiology is the most widely used noninvasive approach for the assessment of myocardial perfusion. The available single-photon emission computed tomography (SPECT) flow agents are characterized by a rapid myocardial extraction and by a cardiac uptake proportional to blood flow. In addition, different positron emission tomography (PET) tracers may be used for the quantitative measurement of myocardial blood flow and coronary flow reserve. The decrease in blood flow, determined by coronary artery stenosis, produces myocardial ischemia leading to perfusion abnormalities detectable by SPECT or PET in the early phase of ischemia. Other imaging techniques, such as contrast echocardiography and magnetic resonance imaging (MRI) have been more recently proposed as alternative methods for the evaluation of myocardial perfusion. Although several technical aspects have to be better defined to use contrast echocardiography in clinical practice, this approach appears promising for the evaluation of myocardial perfusion. MRI has also been proposed for the assessment of myocardial perfusion by measuring the alteration of regional myocardial magnetic properties after the intravenous injection of contrast agents. Due to the high contrast and spatial resolution of the technique, MRI allows differentiating sub-endocardial and sub- epicardial perfusion, emerging as a potential alternative non- ionizing technique to evaluate myocardial perfusion. This review illustrates the noninvasive imaging modalities for the evaluation of myocardial perfusion, underlying advantages and disadvantages of each technique.

KEY WORDS: Myocardial perfusion - Radionuclide imaging - Contrast media - Echocardiography - Magnetic resonance imaging.

A large body of evidence supports the effectiveness of myocardial perfusion imaging (MPI) by different techniques for the management of patients with suspected or known coronary artery disease (CAD). The development of abnormalities associated with CAD generally follows a specific sequence of events. The decrease in blood flow, determined by coronary artery stenosis, produces myocardial ischemia leading to detectable perfusion abnormalities. The progression of CAD leads to wall motion abnormalities as consequences of diastolic dysfunction, followed by regional systolic dysfunction. Thus, the noninvasive evaluation of patients with suspected CAD is based on the early detection of ischemia and its sequential manifestations. In the area of emphasis on cost-effectiveness, optimal utilization of resources requires an accurate evaluation of the incremental amount of information provided by a test, over and above what can be obtained from the standard clinical variables alone. At present, nuclear cardiology is the most widely used noninvasive approach for assessing myocardial perfusion. Other imaging techniques, such as contrast echocardiography and magnetic resonance imaging (MRI) have been more recently proposed as alternative methods for the evaluation of myocardial perfusion.

Pathophysiology of myocardial perfusion

Myocardial perfusion depends on both the driving pressure gradient and the resistance of the vascular bed. Through autoregulation, the coronary bed maintains myocardial perfusion within a narrow range in spite of wide fluctuations in coronary perfusion pressure.1 Hence, despite chronic, progressive coronary artery stenosis, regional blood flow at rest may be unaffected until the stenosis exceeds 90% of the normal vessel diameter.2 In the presence of subcritical coronary stenosis, however, autoregulation is incapable of preserving maximum blood flow during exercise or pharmacological stress test. Thus, in a patient with coronary artery stenosis, when acute myocardial ischemia occurs, the initial abnormality is an imbalance in blood flow between the hypoperfused and normally perfused areas. In response to severe hypoperfusion, myocardial relaxation becomes impaired, providing an early functional indication of ischemia. Impairment of left ventricular relaxation may be followed by abnormalities of regional contraction during systole and subsequently by ischemic chest pain.3-6

Coronary angiography is considered the "gold standard" for evaluating the presence and the severity of coronary stenosis. Although the anatomical extent of disease is best demonstrated by coronary angiography, perfusion imaging provides hemodynamic significance of epicardial stenosis. In addition to a complementary assessment of physiological significance of the disease, noninvasive imaging provides information on important features, such as endothelial and small vessel functions. Discrepancies between coronary anatomy and perfusion do not necessarily indicate a failure in the assessment of either; instead they indicate the complexity of the relationship between anatomical and physiological conditions. If the detection of anatomic coronary artery stenosis were the only objective in the evaluation of patients with suspected CAD, all of these patients would be examined by angiography alone. There is, however, a continuing need for noninvasive testing that clarifies the physiologic significance of a coronary artery stenosis, that provides powerful prognostic data, and permits an accurate detection of the disease with lower cost and greater patient convenience as compared to coronary angiography. Because the resistance to blood flow through a stenotic lesion depends on a number of lesion characteristics, the physiological significance of coronary lesions of intermediate severity is often difficult to determine from angiography alone. Importantly, coronary lesions of intermediate severity have a differential flow reserve that decrease as stenosis increases. Furthermore, hyperemic blood flow is significantly lower in regions supplied by vessels with lesions >90% than in those supplied vessels with lesions <50%.7 Angiographic evidence of stenosis severity is reported to show no or poor correlation with clinical or physiologic parameters such as coronary flow reserve (CFR) and reactive hyperemia.2 This explains the increasing importance of perfusion imaging in cardiovascular medicine.

Radionuclide myocardial perfusion imaging

In patients with CAD, myocardial blood flow abnormalities precede contractile dysfunction. Therefore, perfusion imaging by single photon emission computed tomography (SPECT) or positron emission tomography (PET) might become abnormal earlier in the course of ischemia as compared with other modalities which are dependent on induction of abnormal regional contraction. Clinical studies documented the hypothesis that coronary artery stenosis may, under some conditions, impair blood flow during exercise or pharmacological stress test without producing sufficient ischemia to induce a regional contractile abnormality.4, 6 Some patients with CAD develop substantial imbalance of regional myocardial blood flow in the absence of, or prior to, wall motion abnormality. Thus, radionuclide MPI is a useful method for assessing perfusion directly and in earlier stage. The capabilities of radionuclide techniques to assess myocardial perfusion in the presence of coronary artery stenosis are related to the relationship between initial myocardial distribution of a perfusion tracer and corresponding regional blood flow. The available SPECT flow agents are characterized by a rapid myocardial extraction and by a cardiac uptake proportional to blood flow. Thus, myocardial perfusion can be imaged and hypoperfusion can be detected as a relative uptake defect as compared with the normally perfused myocardium. In addition, different PET tracers may be used for the quantitative measurement of absolute or relative myocardial blood flow and CFR.

Myocardial perfusion imaging with SPECT

Thallium-201

The initial myocardial accumulation of thallium-201 (Tl-201) is proportional to regional myocardial blood flow with a high first- pass extraction in the range of 85%. The relation between blood flow and myocardial uptake is almost linear at low and moderate flow level, to at least 3 mL/min/gm. Beyond this level, there appears to be a decrease in the uptake of Tl-201 in relation to blood flow. However, at approximately 3 mL/min/gm, there is a plateau effect such that, despite increases in blood flow, Tl-201 activity does not change. The accumulation and retention of Tl-201 within the myocardium depends on both coronary blood flow and cellular viability. Intracellular uptake of Tl-201 across the sarcolemmal membrane is maintained for as long as sufficient blood flow is present to deliver the tracer to the myocardial cell. Once Tl-201 has entered into myocardial cells, a continuous exchange (washing in and washing out) takes place across the cell membrane. Under conditions of ischemia, the intrinsic washout rate for Tl-201 is reduced. This contributes to equalization of late tracer activity between initially ischemic and initially normally perfused regions and is referred to as tracer redistribution. After Tl-201 injection, the early images obtained immediately reflect the regional distribution of myocardial blood flow. Despite Tl-201 has been the most used tracer to assess myocardial blood flow, its physical characteristics are subopt\imal. The energy level (69 to 83 KeV) is marginally suitable for imaging with conventional gamma camera and makes some problems for attenuation within the body. The relatively long physical half-life (73 hours) and biological half-life (10 days) lead to a radiation dose to the kidneys and only a small amount (74 to 111 MBq) of Tl-201 can be administered.

Technetium-99m sestamibi

The initial myocardial accumulation of technetium-99m (Tc-99m) labeled sestamibi is proportional to regional myocardial blood flow with a first-pass extraction fraction lower than that of Tl-201.8 However, the much higher dose of sestamibi used more than compensates for lower extraction as compared to Tl-201. The relation between regional blood flow and myocardial uptake is to approximately 2 mL/min/m. Above this level, sestamibi myocardial uptake is not linear with increasing flow.9 The myocardial handling of sestamibi is related to its lipophilicity that makes it able to partition across biological membranes. Once sestamibi accumulates within the myocardial cell, it is bound in a relatively stable fashion. The parenchymal cell permeability and volume of distribution of sestamibi are much greater than Tl-201, resulting in a longer residence time within the myocardial cells for sestamibi.10 Therefore, at the time of clinical imaging following tracer injection, net myocardial tracer content is similar for Tl-201 and sestamibi spite of the higher and more rapid extraction of Tl-201. Sestamibi has no definite evidence of differential washout from ischemic and normal tissue. Therefore, images obtained at 1 hour reflect perfusion at the time of injection. The energy level (140 KeV) of Tc-99m is ideal for imaging with conventional gamma camera, decreasing problems for soft tissue attenuation. Moreover, the half- life (6 hours) permits that larger dose can be administered to the patient as compared to Tl-201.

Technetium-99m tetrofosmin

The initial myocardial accumulation of Tc-99m labeled tetrofosmin is proportional to regional myocardial blood flow with a first-pass extraction fraction lower than that of Tl-201 and sestamibi. Myocardial uptake is proportional to blood flow over the physiological range of flow in experimental model. Blood flow and tetrofosmin myocardial activity show a linear relationship to approximately 2 mL/min/m. Above this level, as for sestamibi, tetrofosmin uptake is not linear with increasing blood flow. Furthermore, tetrofosmin demonstrates a plateau during stress at a blood flow level lower than that of sestamibi.11 Following intravenous injection tetrofosmin clears rapidly from the blood. Myocardial extraction from the blood into the myocardium is less efficient than for Tl-201. Tetrofosmin like sestamibi is characterized by a rapid heart uptake and stable retention, without evidence of redistribution for up to 3 hours after injection, even in reversible ischemic segment.12 Tetrofosmin presents the same advantages of sestamibi regarding the energy level, the half-life and the larger doses can be administered to the patient in comparison with Tl-201.

TABLE I.-Sensitivity and specificity of stress myocardial perfusion SPECT in detecting coronary artery disease (≥50% stenosis).

Myocardial perfusion imaging with PET

Rubidium-82

Rubidium-82 (Rb-82) is a cation and its uptake depends on myocardial perfusion. Rb-82 has a short half-life (76 s) which makes it possible to carry out multiple examinations of the same patient within an acceptable time period. Experimental studies suggest that myocardial uptake of Rb-82 is proportional to blood flow up to 2-3 mL/g/min.13 The single-pass extraction of Rb-82 by the myocardium is inversely and nonlinearly related to coronary blood flow. Although the extraction fraction may decrease during periods of myocardial ischemia, the qualitative assessment of relative Rb-82 perfusion defects has correlated well with those obtained from microspheres. The quality of images obtained after intravenous administration of Rb-82 depends on the tracer infusion duration and imaging protocol. Although disappearance of tracer from arterial blood is rapid, infusion system with prolonged administration times results in high myocardial blood-pool activity.

Nitrogen-13 ammonia

Nitrogen-13 (N-13) ammonia is the most commonly used perfusion tracer with PET.14 When injected ammonia is extracted by myocardial tissue with a very high extraction fraction where it is converted to N-13 glutamine. The clearance half time of ammonia activity from the myocardium is slow enough that one can wait until blood pool activity is significantly lower than myocardial activity. Similar to the case for Rb-82, ammonia myocardial extraction is nonlinear and inversely related to blood flow. The myocardial uptake of ammonia reflects absolute blood flows up to 2 to 2.5 mL/g/min and plateaus in the hyperemic range.15 With increasing flow rates, the metabolic trapping involving a carrier mediated-transport becomes rate limiting, reducing the net tissue retention fraction. Ammonia provides excellent quality images of the myocardium, because of the high single-pass extraction (approximately 70% to 80% at physiologic flow rates), the relatively prolonged retention of tracer by the heart (biological half-life of 80 to 400 min) after intravenous administration and the rapid blood-pool clearance.

Oxygen-15 water

Oxygen-15 (O-15) water is a freely diffusible tracer with a short physical half-life (2.1 minutes). To effectively obtain myocardial images, O-15 (because of its short half-life) requires administration of 80-100 mCi/injection, with rapid data acquisition. Quantitative assessment of regional O-15 water perfusion correlates closely with perfusion assessed by microspheres over a wide range of flow.16 Because water is distributed in both the vascular space and myocardium, visualization of myocardial activity with this tracer requires correction for activity in the vascular compartments, which makes the images difficult to interpret visually. The correction is accomplished by acquiring a separate scan that identifies either the intravascular or the myocardial compartments.

Figure 1.-Quantitative display output for the Cedars-Sinai Quantitative Perfusion SPECT (QPS) program. Stress and rest myocardial tomographic images, percent abnormal for defect extent and reversibility, and automatically generated perfusion score output are presented demonstrating a reversible perfusion defect in the distribution of the left anterior descending coronary artery in a patient with coronary artery disease.

Evaluation of coronary artery disease by radionuclide MPI

Myocardial perfusion SPECT is a well-established modality for the evaluation of patients with suspected or known CAD. The basis for the diagnostic application of nuclear testing lies in the concept of Bayesian analysis of disease probability. This analysis requires knowledge of the pretest likelihood of disease, as well as of the sensitivity and specificity of the test. The pretest likelihood or prevalence of disease varies according to age, sex, symptoms and risk factors, and can be directly derived from different databases or computed algorithms.17,18 The algorithm for the purpose of CAD detection provides that patients with an intermediate likelihood of disease will mostly benefit from stress SPECT imaging.19,20 On the other hand, patients with a high likelihood of CAD are generally considered to have an established diagnosis of disease, and would not need radionuclide stress testing for diagnostic purposes. However, nuclear stress testing may be very effective in risk stratification of such patients. In the clinical setting, exercise or pharmacological SPECT imaging is used to elicit changes that may not be apparent under resting conditions.21,22 Published reports have consistently demonstrated that stress SPECT imaging has high sensitivity and specificity for diagnosing the presence of CAD and localizing the anatomic site of coronary artery stenosis.23-34 In many trials Tc-99m labeled imaging agents have been compared to Tl- 201 for the detection of CAD. Despite different physical imaging characteristics, the 3 tracers have comparable overall diagnostic accuracy for identifying CAD, using different forms of stress,25-34 as illustrated in Table I. In addition, perfusion SPECT imaging provides important prognostic information either in patients with suspected or known CAD.35-39

Figure 2.-Quantitative display output for the Cedars-Sinai Quantitative Perfusion SPECT (QPS) program. Stress and rest myocardial tomographic images, percent abnormal for defect extent and reversibility, and automatically generated perfusion score output are presented demonstrating an irreversible perfusion defect in the distribution of the left anterior descending coronary artery in a patient with prior myocardial infarction.

TABLE II.-Intra- and interobserver reproducibility of quantitative analysis of myocardial perfusion SPECT in patients with coronary artery disease.

PET perfusion tracers have short physical half-lives providing some practical advantages over SPECT. In particular, PET offers the possibility of acquiring repeated myocardial blood flow measurements, in the same patient in the same scanning session within a reasonable time (1 to 2 hours). Several studies demonstrated high diagnostic accuracy of PET for the detection of CAD.40, 41 Based on available results, a joint task force have found a sensitivity of 87% to 97% with a specificity of 78% to 100% for PET as compared to 89% and 76% for SPECT, respectively.42 Larger studies with comparative expertise in both PET and SPECT imaging are required to determine more precisely the relative diagnostic efficacy of the 2 techniques.

Figure 3.-Quantitative gated SPECT (QGS) analysis of the patient in Figure 1. The left ventricular ejection fraction is normal at 48%. There is quantitative evidence of abnormal of left \ventricular wall motion with a summed wall motion score (SMS) of 4 and a summed wall thickening score (STS) of 7.

Strength and weakness of radionuclide MPI

The most recent nuclear medicine computer systems allow complex procedures, such as image reconstruction, quantification and display, to be performed rapidly. Because the tomographic projections are easily standardized from patient to patient, quantification of myocardial tomograms and comparison to normal limits, established in population of healthy subjects, can be accomplished. Quantification makes possible to document objectively specific patterns of abnormal perfusion or soft-tissue attenuation, suspected from subjective image interpretation (Figure 1 and 2). A further advantage of quantification approach is the standardization of image interpretation resulting in a reduction of intra- and interobserver variability (Table II). In addition, radionuclide imaging can be performed using gated-SPECT allowing a combined evaluation of perfusion and function, an important goal in routinely clinical use (Figure 3 and 4). A potential limitation of MPI with SPECT tracers is that absolute myocardial blood flow in mL/min/kg cannot be measured. However, with current SPECT imaging technology, abnormal myocardial perfusion is detected in most of patients. Nuclear imaging methods have the intrinsic disadvantage of requiring the use of radioactive materials. It has been documented that radionuclide MPI is safe, particularly in comparison with invasive procedures. In particular, no significant adverse medical effects have been documented resulting from the use of radioactive agents in standard diagnostic nuclear medicine procedures. The complication rate of dynamic exercise and pharmacological stress tests is well established (at most 0.01% deaths and 0.02% morbidity).43-46 Therefore, except in patients -with unstable heart disease or other contraindications to stress, the risk is not considered significant. However, assurance of safe use of radioactive materials requires a detailed radiation safety program, which adds to the costs of nuclear medicine procedures.

Figure 4.-Quantitative gated SPECT (QGS) analysis of the patient in Figure 2. The left ventricular ejection fraction is abnormal at 29%. There is quantitative evidence of abnormal of left ventricular wall motion with a summed "wall motion score (SMS) of 48 and a summed wall thickening score (STS) of 29.

Contrast echocardiography

A good stress echocardiogram depends on accessible acoustic window. In patients with high thoracic impedance and with difficult acoustic window ultrasound evaluations have a reduced sensitivity and specificity. Improvement of echocardiographic images may be obtained by contrast echocardiography. A contrast agent or even saline infusion is characterized by air-filled microbubbles with acoustic reflectivity different from cardiovascular structures; this property allows visualization of intracardiac or vascular structures. Main contrast agent and their composition are shown in Table III.

Contrast echocardiography is useful in the visualization of the endocardial border, in the demonstration of myocardial perfusion, in the identification of an intracardiac shunt, in the evaluation of unknown cardiovascular structures and in the recording of Doppler flow velocities. The visualization of the endocardial border was the first clinical indication for commercially available contrast agents (Albunex and Optison) in human studies. Several investigations demonstrated that the use of microbubbles might improve the definition of the endocardial border until 90%.47 Adequate visualization of the endocardial border is necessary to assess global and regional left ventricular systolic function and to perform a diagnostic stress test echocardiography.48

TABLE III.-Main contrast agent and their composition.

Myocardial perfusion imaging with contrast echocardiography

The evaluation and quantification of myocardial perfusion are the most exciting applications for contrast echocardiography. A dense microvascular circulation characterizes the myocardium. Moreover, the blood supply of microvascular circulation depends on the large epicardial coronary arteries. If a contrast agent can pass through the myocardial blood vessels, the degree of the acoustical reflectivity from the bubbles within the microvascular circulation detected by two-dimensional echocardiography should correlate with the extent of coronary blood flow (Figure 5). An ideal contrast agent for detection of myocardial perfusion should have as characteristic, safety and tolerability by the patient, and ability to pass through the pulmonary capillaries. Moreover, this ideal agent should be identifiable with echocardiography, not change cardiac hemodynamic, be resistant to variations in size when it comes in contact with blood (because ultrasound backscatter is related to the sixth power of bubble radius) and have low solubility and non-diffusibility. The use of contrast echocardiography requires an understanding of the backscatter properties of microbubbles and the physics of ultrasound. Microbubbles are destroyed by constant exposure to an ultrasound beam. Intermittent ultrasound imaging at a certain interval minimizes the rupture of microbubbles and permits better visualization of myocardium and a 7-times reduction of agent contrast quantity.49 Microbubbles exposed to low power ultrasound keep their volume while microbubbles exposed to higher power ultrasound change their volume. Volume variation entity is greatest for a frequency called resonance frequency. Microbubbles exposed to their resonance frequency emit multiple of harmonics frequency (f). The backscatter property of microbubbles is their ability to resonate at frequencies that are multiples of the transmitted frequency (2f, 3f, and 4f). Because other surrounding structures (myocardium and valves) reflect only the original transmitted frequency (10, imaging is obtained at a frequency twice (2f). This has been defined second harmonic imaging,50 in contrast to fundamental imaging that identifies structures with backscatter of the transmitted frequency (10. The combined approach of second harmonic imaging and transient intermittent gating improves the detection of microbubbles in the cardiac chambers and myocardium. Intramyocardial coronary arteries may be visualized by second harmonic imaging of an echocardiographic contrast agent. A Doppler study with a sample volume in the vessels demonstrated a typical coronary flow signal at baseline and appropriately increased flow velocity after the intracoronary administration of adenosine.

Figure 5.-Myocardial perfusion assessed by contrast echocardiography in a healthy volunteer. Echocardiographic image shows homogeneous distribution of the contrast agent within the left ventricular myocardial walls.

Evaluation of coronary artery disease by contrast echocardiography

The goal of contrast echocardiography is the evaluation of myocardial perfusion. Traditional imaging has not been always successful in demonstrating myocardial perfusion after intravenous injection of contrast agent. Although several technical aspects has to be defined to use contrast echocardiography in clinical practice, this approach appears promising for the detection of myocardial perfusion abnormalities, and useful in the evaluation of CAD, estimation of myocardial risk area, evaluation of reperfusion therapy, and determination of myocardial viability. In the acute phase of myocardial necrosis a perfusion defect may be detected by contrast echocardiography; this defect disappears after effective reperfusion therapy. The not significant or absent increase of myocardial contrast after acute reperfusion therapy (by thrombolytic therapy or primary percutaneous coronary intervention) is associated with no reflow phenomenon.51 Similarly, contrast echocardiography may identify intact microvascular circulation in the myocardium. The intact microvascular circulation in akinetic myocardium is good evidence for myocardial viabil ity. Contrast echocardiography is sensitive for detecting myocardial viability but it has a low specificity in predicting recovery of left ventricular function after revascularization in comparison with low-dose dobutamine stress echocardiography.52,53 A combination of low dose dobutamine and contrast echocardiography increases sensitivity and specificity to detect viable myocardium.

Strength and weakness of contrast echocardiography

In general, advantages of echocardiography include no radiation exposure for patients and operators, wide availability, easy performance, and the possibility of using contrast agents to improve sensitivity and specificity in clinical settings. The major disadvantages of the technique are represented by operator dependency, lack of reproducibility and technical difficulties to obtain good quality images in patients with high thoracic impedance.

Magnetic resonance imaging

Diagnosis of CAD is a major challenge for noninvasive medical imaging and an active area of research is cardiac MRI. MRI combining real time ultra fast imaging acquisition such as fast gradient echo or echo-planar imaging techniques with the bolus injection of a contrast agent is emerging as an alternative noninvasive, non ionizing technique for evaluating myocardial perfusion at rest and during pharmacological stress.54 Although the assessment of myocardial perfusion with MRI has been successfully performed on conventional whole body scanners, recent developments in hardware and software have resulted in improved electrocardiographic triggering, better gradient performance and faster acquisition sequences. These developments have led to substantial reductions in imaging time while preserving or improving image quality. In particular, high performance gradients reduce image acquisition times and artifacts resulting from cardiac motio\n and increase signal to noise ratio.55,56 Main field strength of 1.5 Tesla and a minimum gradient rise time of 25 mTm up to 70 mTm are therefore recommended in order to obtain good quality cardiac MR images.

Myocardial perfusion imaging with magnetic resonance imaging

During the last years, MRI has been used for the assessment of myocardial perfusion by measuring the alteration of regional myocardial magnetic properties after the intravenous injection of contrast agents. The most commonly used contrast agents are chelates of gadolinium (gadopentate, gadodiamide and gadotetriole), which shorten Tl relaxation time leading to an increase in signal intensity on Tl weighted MR images. These agents are large molecules that rapidly diffuse from the intravascular space into the interstitium remaining in the extracellular space and are unable to enter cells provided that the tissue cell membranes are intact.57 Although during the first pass more than 30% of the contrast agent enters the interstitium, the myocardial concentration of the contrast agent is primarily determined by myocardial blood flow.58 After the intravenous bolus administration of the contrast agent, normal myocardium will show increased signal intensity, followed by contrast washout (Figure 6). Conversely, areas supplied by a coronary vessel with a high-grade stenosis will show reduced or delayed signal intensity. With the techniques currently available it is possible to obtain accurate characterization of regional myocardial perfusion through repetitive acquisition of images over the entire heart with high temporal resolution allowing capturing the first pass of the contrast agent through the myocardium. First- pass imaging is usually completed within 20-30 s and is typically performed during a prolonged breath-hold. In the early 1990s single- slice gradient-echo sequences were largely used for myocardial perfusion MRI studies in human subjects. More recently, the application of echo-planar, ultrafast multislice techniques has significantly improved the diagnostic capability of firstpass contrast-enhanced MRI.59 A standard sequence currently in use is the inversion recovery snapshot fast low angle shot (FLASH) that is able to provide a high degree of spatial resolution, high signal-to- noise ratio and good image contrast.60 Accurate characterization of regional myocardial perfusion necessitates repetitive acquisition of images over the entire heart with high temporal resolution to capture the first pass of the contrast agent through the myocardium. Usually 3 to 7 short axis views of the left ventricle are acquired covering 16 out of 17 possible myocardial segments. Image acquisition is repeated for several consecutive heartbeats to follow the first pass of the contrast agent. Evaluation of perfusion reserve implies that a second set of images is acquired after the intravenous administration of a pharmacological stress agent such as dipyridamole or adenosine.61,62 In clinical practice, the standard dose for dipyridamole is 0.56 mg/kg over 4 minutes. Imaging is performed at 2 min during the infusion. Adenosine is infused at 140 mg/kg for 6 minutes and imaging is usually started after 3 min. Both vasodilators are commonly used for perfusion imaging with MRI. However, adenosine might be preferred because, although in many countries it is more expensive than dipyridamole, its extremely short half-life of less than 10s ensures that adverse effects are short-lived. Dipyridamole has a short half-life of 30 min so that prolonged ischemia may be provoked and persist despite aminophylline administration. Dobutamine has also been proposed as an alternative stress agent for MPI with MRI however results have been less satisfactory.55,63

Figure 6.-First-pass contrast-enhanced MR myocardial perfusion images acquired with a single-shot turbo field-echo, echo-planar sequence in the left ventricular short axis views after the intravenous administration of Gadolinium-DTPA (0.1 mmol/kg) in a healthy volunteer. MR images show the bolus transit of the contrast agent through the right ventricle (A), the left ventricle (B) and the myocardium (C) of the left ventricle that shows homogeneous signal enhancement under resting conditions.

A variety of postprocessing methods have been used to extract information from perfusion images with MRI. These include qualitative image interpretation, that provide a comprehensive and rapid interpretation that is ideal for clinical use, and semiquantitative methods, that require the definition of myocardial regions of interest with extraction of signal-intensity time curve data. Using both methods, indexes of normal versus abnormal myocardial perfusion can be subsequently extracted from these curves in order to obtain an objective assessment of relative regional perfusion.

Several studies have investigated the usefulness of perfusion MRI for the diagnosis of ischemic heart disease based on a qualitative or semi-quantitative evaluation of first pass kinetics of the contrast media.64 In particular, several semi-quantitative flow indices according to the indicator dilution theory have been proposed and validated.65 These indices involved fitting to a gamma variate function all points on the signal intensity time curve between time O and the instant when the signal intensity increase reaches peak level and decreases to 70% of peak. From this, they derive the mean transit time, the time to reach peak signal intensity of the curve, and the initial slope of the signal intensity change during contrast wash-in.65 Absolute quantitative analysis of myocardial perfusion require the use of complex kinetic models to take into account the complex distribution properties of gadolinium in the heart and still remains a difficult goal to achieve. Such modeling has been performed by several groups and has been validate in animals and in a small patient population.66 However, standardization of analysis methods is needed to improve the consistency of data.

Evaluation of coronary artery disease with magnetic resonance imaging

Several clinical studies have been performed to evaluate the diagnostic potential of MRI for MPI under resting or stress condition.54,;60-67 Lauerma et al.,60 using a fast gradient echo multislice sequence in a highly selected patient populations with documented single-vessel CAD, reported a close correlation between dipyriclamole Tl-201 scintigraphy and contrast-enhanced multislice MRI for detecting regional perfusion defects and assessing the effects of revascularization procedures.60 However, in other studies the application of a multislice approach to a mixed unselected study population yielded low sensitivity and specificity (<50%).68,69 Schwitter etal.61 reported that multisection MR assessment of myocardial perfusion using a hybrid echo planar approach provides 91% sensitivity and 94% specificity in the detection of CAD as defined by PET with N-13 ammonia. In the same study, sensitivity and specificity were 87% and 85%, respectively, in comparison with quantitative coronary angiography.61 The best results for the detection of CAD by MR perfusion imaging were obtained when contrast material wash-in was assessed in the sub-endocardial layer, which is the region most sensitive to an ischemic challenge. Moreover, the amount of compromised myocardium, as assessed by MRI, closely agreed with PET measurements providing an accurate estimate of the disease extent and important prognostic information essential for patient management. In a more recent investigation, Wagner et al.70 compared SPECT performed with a dual isotope acquisition protocol with contrast enhanced MRI in a canine infarct-reperfusion model as well as in a group of 91 patients with known or suspected CAD. A recent study by Panting et al.71 used cardiac MRI to examine the perfusion patterns at rest and during adenosine stress in patients with syndrome X in comparison to normal control subjects. They used the normalized upslope of myocardial signal enhancement to derive the myocardial perfusion index that allows a quantitative perfusion analysis. The myocardial-perfusion reserve index, defined as the ratio of the myocardial perfusion index during stress to the index at rest, was also calculated.71 In the control subjects, the myocardial perfusion index increased during adenosine infusion. Conversely, in patients with syndrome X, the myocardial perfusion index did not change significantly in the sub-endocardium but increased in the sub-epicardium. These data suggest that chest pain experienced by patients with syndrome X has an ischemic origin due to microvascular obstruction and that MRI is able to detect sub- endocardial hypoperfusion during the intravenous administration of adenosine.

Future directions of MPI with MR include the optimization of current pulse sequences and the development of new methods to acquire images with improved signal to noise ratio, sufficient temporal resolution and complete cardiac coverage. Furthermore, newer contrast agents, including intravascular, infarct-avid, and intracellular agents are under investigation to assess their potential advantages over the current interstitial, gadolinium- based agents. Spinlabel gradient-echo imaging techniques have been proposed as an alternative approach for the quantitative measurement and mapping of myocardial perfusion in small animals and in humans.72,75

Strength and weakness of magnetic resonance imaging

Advantages of MRI over other noninvasive techniques include the higher contrast and spatial resolution that allows to differentiate sub-endocardial and sub-epicardial perfusion and the use of non- ionizing energies that allow the measurements to be repeated regularly without any adverse effect for the patients. There is also a reduced operator-dependency if a semiquantitative computerized postprocessing method is used. In addition, the MR perfusion measurements can be perf\ormed combined with an evaluation of global left ventricular function and regional wall thickening allowing a "onestop shop" examination in less than 1 hour. One of the main obstacles for a wider use of MRI has been the lack of large multicenter clinical outcome data based on standardized protocols and analysis. However, further advances in MRI hardware and software and improvements in methods for perfusion analysis, including faster and user-independent techniques, will certainly allow a rapid implementation of perfusion MRI in the noninvasive assessment of patients with CAD.

Conclusions

Different imaging methods are currently available for the assessment of regional myocardial perfusion in patients with suspected or known CAD. At present, nuclear cardiology is the most widely used and validated noninvasive approach for assessing myocardial perfusion. Other imaging techniques, such as contrast echocardiography and cardiac MRI have been more recently proposed as alternative methods for the evaluation of myocardial perfusion. However, the relatively limited validation of current results has restricted the widespread clinical applicability of myocardial perfusion contrast echocardiography and MRI. With the introduction of newer contrast media, technologic improvements on hardware and software, and the enhancement of quantitative analysis, contrast echocardiography and MRI might become a clinical tool for assessment of myocardial perfusion imaging in the future.

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A. CUOCOLO 1,2, W. ACAMPA 1,2, M. IMBRIACO 1, N. DE LUCA 3, G. L. IOVINO 3, M. SALVATORE 1

1 Department of Biomorpbological and Functional Sciences Institute of Biostructure and Bioimages of the National Council of Research

Federico II University of Naples, Naples, Italy

2 IRCCS Neuromed, Pozzilli, Isernia, Italy

3 Department of Clinical Medicine, Cardiovascular and Immunological Sciences

Federico II University of Naples, Naples, Italy

Address reprints requests to: A. Cuocolo, MD, Dipartimento di Scienze Biomorfologiche e Funzionali, Universit Federico II, Via S. Pansini 5, I-80131 Napoli, Italy. E-mail: cuocolo@unina.it.

Copyright Edizioni Minerva Medica Mar 2005

Source: Quarterly Journal of Nuclear Medicine, The

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