Applied Radiology

The evaluation of myocardial perfusion and ventricular function provides important diagnostic and prognostic information in the assessment of patients with known or suspected cardiovascular disease. Cardiovascular nuclear imaging represents accurate, safe, relatively inexpensive, and widely accepted noninvasive modalities for assessing these physiologic parameters. The results of these studies frequently influence clinical decisions in the medical care of these patients.

Myocardial perfusion is assessed by the administration of radiopharmaceuticals that are extracted from the blood pool and distributed intracellularly within the myocardial tissue (e.g. thallium-201 [Tl-201] or technetium-99m [Tc-99m] agents), whereas, historically, ventricular function is assessed while the selected radiopharmaceutical is still within the circulating blood pool. Conventionally, ventricular function is evaluated by multigated acquisition studies (MUGA) with either Tc-99m-labeled red blood cells or human serum albumin that remains in the blood pool for a prolonged period of time, or by first-pass radionuclide angiography (RNA) that requires the administration of a high dose of a radiopharmaceutical agent that needs to remain in the blood pool for only a brief period of time. Several Tc-99m-labeled agents have been used for first-pass RNA, including sodium pertechnetate, diethylenetriamine penta-acetic acid (DTPA), and sulfur colloid, as well as other radionuclides such as gold-195m and iridium-191m. Historically, relative to the choices of radiopharmaceuticals, as noted above, a decision had to be made prior to testing whether to assess myocardial perfusion or ventricular function. In order to fully assess both of these parameters, two separate studies had to be performed at different times with the administration of two different radiopharmaceuticals.

Myocardial perfusion

Myocardial perfusion imaging has been used as an adjunct to cardiovascular stress testing for many years and is a well established imaging modality for the assessment of myocardial ischemia. Myocardial perfusion studies can be acquired as planar images, but the preferred imaging modality is single photon emission computed tomography (SPECT). The two most commonly used classes of radiopharmaceuticals for perfusion imaging are Tl-201 and Tc-99m agents.

Thallium-201, a cyclotron-produced radionuclide which acts as a potassium analog and is extracted by the myocardium relative to myocardial blood flow, has been used extensively for many years for evaluating patients for myocardial ischemia and viability. All of the early investigations, dating back to the 1970s, upon which the foundation for myocardial perfusion imaging has been built, were based on the pharmacokinetics of Tl-201. Some limitations of this agent include its low photon energy of approximately 80 keV (the characteristic x-ray of mercury-201) and its relatively long half-life of 73 hours, which limits the average dose of this myocardial perfusion tracer to approximately 4.0 mCi (148 MBq).

Technetium-99m agents also are distributed in the myocardium in relationship to regional myocardial blood flow. These radiopharmaceuticals offer several advantages over Tl-201. They are available in a kit form and can be prepared on site, with Tc-99m eluted from a standard molybdenum-99/Tc-99m gen-erator. The optimal six-hour half-life of Tc-99m allows for a significantly higher dose of radioactivity to be administered (as much as 30 mCi [1,110 MBq]), which results in better imaging statistics with higher count rates than what is obtainable with Tl-201.

Myocardial perfusion scintigraphy with either Tl-201 or Tc-99m agents is an accurate technique for the diagnosis of coronary artery disease. Although these two perfusion tracers have different characteristics and pharmacokinetics, they have comparable accuracy in their diagnostic capabilities. Pooled data for exercise Tl-201 SPECT imaging has an average sensitivity of 92% and a specificity of 68% for the diagnosis of coronary artery disease.1 Comparable results are noted from pooled data for Tc-99m sestamibi SPECT imaging, which has an average sensitivity of 89% and a slightly higher specificity of 90% for the detection of coronary artery disease.2

In addition to demonstrating its value in the diagnosis of coronary artery disease, myocardial perfusion imaging also has been shown to be valuable in establishing patient prognosis and risk stratification in a variety of clinical settings. In patients with stable coronary artery disease, the number of ischemic myocardial segments on perfusion imaging has been shown to be a powerful predictor of future cardiac events.3,4 Multiple studies have demonstrated that a normal myocardial perfusion imaging study predicts a risk of only approximately 1% annual cardiac event rate.5 Thus, the abnormal and the normal myocardial perfusion imaging study have significant prognostic power for cardiac events as related to the extent of perfusion abnormalities. In patients who have had thrombolytic therapy, five-year mortality is significantly higher in patients who demonstrate large perfusion defects than in those with small perfusion defects.6 Finally, the presence of reversible ischemia by myocardial perfusion scintigraphy also has been found to be a significant predictor of peri-operative cardiac events in patients undergoing non-cardiac surgery.7 Therefore, the information provided to the clinical services by myocardial perfusion imaging studies in patients with known or suspected coronary artery disease has become an important factor in the subsequent medical management of these patients.

Combined myocardial perfusion and ventricular functional imaging

As early as 1984, using Tl-201 for perfusion and gold-195m for first-pass RNA,8 and later in 1988, using Tl-201 for perfusion and iridium-191m for first-pass RNA,9 assessment of myocardial perfusion and ventricular function was performed simultaneously as one test, but the injection of two separate radionuclides was still required. Due to technical considerations, these techniques were not popular or widely used.

The introduction of Tc-99m-labeled radiopharmaceuticals for myocardial perfusion imaging ushered in a new era of enhanced capabilities for performing the simultaneous assessment of myocardial perfusion and ventricular function. Technetium-99m agents have been shown to be reliable radiopharmaceuticals for the assessment of myocardial perfusion,10-12 one of which, Tc-99m sestamibi, also has been shown to be reliable in the assessment of left ventricular function by first-pass RNA.13,14 The ability to administer a higher dose of radioactivity and to perform simultaneous assessment of myocardial perfusion and ventricular function with a single injection of a Tc-99m-labeled radiopharmaceutical13,15 has made these combined procedures more widely available, and has led to the development of novel techniques for acquiring this information with a single radiopharmaceutical injection. The modalities for assessing ventricular function that can be performed in conjunction with myocardial perfusion, include first-pass RNA and gated SPECT perfusion imaging.

First-pass radionuclide angiography-First-pass RNA is a well established nuclear imaging technique that has been used for many years for the assessment of ventricular function. This technique requires the delivery of a compact bolus of radiopharmaceutical into the central circulation, and the ability to record high count rates over a brief interval of time as the administered tracer makes its first pass sequentially through the superior vena cava, the right ventricle, the lungs, the left ventricle, and the aorta. It is essential that the tracer administered for first pass RNA studies be delivered as a compact bolus injection. Image quality is directly related to the compactness of the bolus injection. The temporal resolution required for processing the final data depends upon a compact transit of the bolus of radioactive tracers. Although this procedure can be performed with a large gauge catheter in an antecubital vein in order to increase the likelihood for a good compact bolus injection, the preferable sight for injection of the first-pass RNA tracer is via a 20-gauge short angiocath in an external jugular vein. In our experience, nuclear medicine technologists have become proficient in the insertion of external jugular venous catheters, and this approach has been widely accepted by patients referred to nuclear cardiology for these studies. Injection of tracer into a more peripheral vessel, such as in the dorsum of the hand, cannot maintain a good bolus effect, and this site generally is suboptimal for the performance of these studies. First-pass RNA is optimally acquired by a multi-crystal gamma camera that is specially designed for rapid detection of high count rates such as those encountered during first-pass RNA studies.

When Tc-99m sestamibi is injected for perfusion imaging, whether the study is being performed as a one-day or a two-day protocol,16 there is adequate activity (minimal injected dose averages 10 mCi [370 MBq]) to obtain a first-pass RNA study. When rest and stress first-pass RNA studies are done in conjunction with perfusion imaging using a Tc-99m agent, the resting study is performed in the anterior projection with the patient standing or recumbent, depending upon whether the stress portion of the study is done with bicycle or treadmill exercise or with intravenous dobutamine. The stress first-pass study is acquired at the peak effect of intravenous dobutamine or at peak exercise on the bicycle or treadmill. Patient motion at peak exercise may present somewhat of a problem. However, motion can be corrected by a computer software program that can track an isolated source of a second radionuclide which is attached to one of the electrocardiographic chest leads and has a different photon energy than Tc-99m (e.g. iodine-125 or americium-241). The first-pass RNA study is acquired in such a brief interval that it represents almost a snapshot of left ventricular function at the true peak of stress.

Various measurements can be derived from the first-pass data, including global and/or regional ventricular ejection fractions, ventricular wall motion, left ventricular end systolic and end diastolic volumes, and cardiac output. The ante-rior projection allows for segmental wall motion analysis of the anterior wall, inferior wall, and apex of the left ventricle. Rest and exercise studies can be compared in order to evaluate for changes that may occur in any of these parameters (figure 1). The left ventricular ejection fraction (LVEF) at peak exercise has been shown to be a powerful prognostic indicator in patients with coronary artery disease.17 Therefore, this study has become an important adjunct to the standard perfusion examination in the clinical assessment of many of these patients.

Gated SPECT myocardial perfusion-Gated SPECT myocardial perfusion imaging with Tc-99m sestamibi is a relatively new modality in cardiovascular nuclear medicine.18 The success of this adjunctive functional technique is also related to the higher count rates provided by the Tc-99m-labeled radiopharmaceuticals for myocardial perfusion. Many current SPECT imaging systems have the capability of acquiring gated perfusion studies. As with a MUGA study, the acquisition of the perfusion study is synchronized with the patient's electrocardiogram, with the image acquisition divided into eight frames per R-R interval and subsequently reviewed in a cine format. The time for image acquisition is not significantly lengthened by acquiring a perfusion study in a gated format, and the data does provide additional functional information that allows for the assessment of left ventricular wall motion (best evaluated on a black-and-white monitor); left ventricular wall thickening, as manifested by the degree of the increase in regional intensity of the left ventricular myocardium during the cardiac cycle (best evaluated on a color monitor); and calculation of an LVEF (figure 2).19-21 Chua et al20 have correlated gated SPECT assessment of regional wall motion and wall thickening with echocardiography. They found exact agreement in 91% of studies for wall motion and in 90% of studies for wall thickening. The stress gated SPECT study, in contrast to a stress first-pass RNA, is acquired approximately 30 minutes after peak stress and, therefore, does not provide the snapshot of left ventricular function at peak stress as does the first-pass RNA study.

Benefits of simultaneous perfusion and functional imaging-The left ventricular ejection fraction probably is the single most important measurement of cardiac performance. It is a major indicator of patient prognosis and is an important factor in risk stratification. The LVEF has been shown to be a powerful prognostic indicator of survival in patients with coronary artery disease. Analysis of data from the Coronary Artery Surgery Study (CASS) Registry has demonstrated progressively increasing mortality rates as the resting LVEF decreases in patients on medical therapy.22 In this study, four-year survival was 92% in patients with an LVEF of 50% or more, 83% in patients with an LVEF of 35 to 49%, and only 57% in patients with a LVEF of less than 35%. Prognostic data also have been reported from results of LVEF determined during exercise in patients with coronary artery disease. Data reported by Lee et al17 demonstrated that the LVEF during exercise, which relates to the extent of myocardial ischemia, provides significant incremental prognostic information relative to coronary angiography and proved to be a powerful predictor of patient survival. With a mean follow-up of 5.4 years, patient survival progressively declined in proportion to a decline in the exercise LVEF below 50%.

It has been demonstrated that regional myocardial perfusion with Tc-99m sestamibi SPECT provides significant incremental information over that provided by the exercise EKG alone, and assessment of regional myocardial function from the exercise first-pass RNA provides further significant incremental information over that provided by the perfusion study in predicting the anatomical extent of coronary artery disease.23 Borges-Neto et al, from our laboratory, also have demonstrated that combined studies of myocardial perfusion and left ventricular function by first-pass RNA can significantly improve the prediction of the extent of coronary artery disease, adding 31% of predictive information beyond that of electrocardiographic and clinical data.24

Fixed myocardial perfusion defects that result from artifact due to diaphragmatic attenuation or overlying soft-tissue attenuation (breast, obesity, pectoralis muscles) are common occurrences in myocardial perfusion imaging. These artifacts can decrease test specificity when they are incorrectly interpreted as regions of prior myocardial infarctions. Normal myocardium that demonstrates attenuation artifact on perfusion imaging also should demonstrate normal wall thickening and wall motion, whereas regions of myocardial infarction should demonstrate significantly diminished-to-absent wall thickening and wall motion. Thus, correlation of fixed perfusion defects with corresponding segmental functional analysis by first-pass RNA (wall motion) (figure 3) or gated SPECT perfusion (wall motion and wall thickening) can increase the level of confidence in the analysis of the perfusion defects on the static myocardial perfusion images. Using gated SPECT evaluation of fixed myocardial perfusion defects, DePuey and Rozanski have reported an improvement in their false positive rate for regional myocardial infarction from 14% to 3%.25

The combination of ventricular functional imaging with myocardial perfusion imaging provides additional incremental information that can assist in the diagnosis and prognostic determination of patients with known or suspected coronary artery disease. The ability to acquire perfusion and functional images with a single injection of tracer should result in wider application and acceptance of simultaneous first-pass RNA and/or gated SPECT imaging with myocardial perfusion imaging. AR

References

1. Beller GA: Current status of nuclear cardiology techniques. Curr Probl Cardiol 16:451-535, 1991.

2. Verani MS: Thallium-201 and technetium-99m perfusion agents: Where are we in 1992? In: Zaret BL, Beller GA (eds): Nuclear Cardiology - State of the Art and Future Directions, pp 216-224.

St. Louis, Mosby, 1993.

3. Brown KA, Boucher CA, Okada RD, et al: Prognostic value of exercise thallium-201 imaging in patients presenting for evaluation of chest pain. J Am Coll Cardiol 1:994-1001, 1983.

4. Ladenheim ML, Pollock BH, Rozanski A, et al: Extent and severity of myocardial hypoperfusion as predictors of prognosis in patients with suspected coronary artery disease. J Am Coll Cardiol 7:464-471, 1986.

5. Brown KA: Prognostic value of myocardial perfusion imaging: State of the art and new developments. J Nucl Cardiol 3:516-537, 1996.

6. Cerqueira MD, Maynard C, Ritchie JL, et al: Long-term survival in 618 patients from the Western Washington Streptokinase in Myocardial Infarction trials. J Am Coll Cardiol 20:1452-1459, 1992.

7. Leppo J, Plaja J, Gionet M, et al: Noninvasive evaluation of cardiac risk before elective vascular surgery. J Am Coll Cardiol 9:269-276, 1987.

8. Narahara KA, Mena I, Maublant JC, et al: Simultaneous maximal exercise radionuclide angiography and thallium stress perfusion imaging. Am J Cardiol 53:812-817, 1984.

9. Verani MS, Lacy JL, Ball ME, et al: Simultaneous assessment of regional ventricular function and perfusion utilizing iridium-191m and thallium-201 during a single exercise test. Am J Cardiac Imaging 2:206-213, 1988.

10. Taillefer R, Dupras G, Sporn V, et al: Myocardial perfusion imaging with a new radiotracer, technetium-99m-hexamibi (methoxy isobutyl isonitrile): Comparison with thallium-201 imaging. Clin Nucl Med 14:89-96, 1989.

11. Iskandrian AS, Heo J, Kong B, et al: Use of technetium-99m isonitrile (RP-30A) in assessing left ventricular perfusion and function at rest and during exercise in coronary artery disease, and comparison with coronary arteriography and exercise thallium-201 SPECT imaging. Am J Cardiol 64:270-275, 1989.

12. Berman DS, Kiat H, Maddahi J: The new 99m-Tc myocardial perfusion imaging agents: 99m-Tc-sestamibi and 99m-Tc-teboroxime. Circulation 84(suppl 1):I-7-I-21, 1991.

13. Baillet GY, Mena IG, Kuperus JH, et al: Simultaneous technetium-99m MIBI angiography and myocardial perfusion imaging. J Nucl Med 30:38-44, 1989.

14. Williams KA, Taillon LA, Draho JM, et al: First-pass radionuclide angiographic studies of left ventricular function with technetium-99m-teboroxime, technetium-99m-sestamibi and technetium-99m-DTPA. J Nucl Med 34:394-399, 1993.

15. Borges-Neto S, Coleman RE, Potts JM, et al: Combined exercise radionuclide angiocardiography and single photon emission computed tomography perfusion studies for assessment of coronary artery disease. Semin Nucl Med 21:223-229, 1991.

16. Borges-Neto S, Coleman RE, Jones RH: Perfusion and function at rest and treadmill exercise using technetium-99m-sestamibi: Comparison of one- and two-day protocols in normal volunteers.

J Nucl Med 31:1128-1132, 1990.

17. Lee KL, Pryor DB, Pieper KS, et al: Prognostic value of radionuclide angiography in medically treated patients with coronary artery disease. Circulation 82:1705-1717, 1990.

18. Mannting F, Mannting MGM: Gated SPECT with technetium-99m-sestamibi for assessment of myocardial perfusion abnormalities. J Nucl Med 34:601-608, 1993.

19. DePuey EG, Nichols K, Dobrinsky C: Left ventricular ejection fraction assessed from gated technetium-99m-sestamibi SPECT. J Nucl Med 34:1871-1876, 1993.

20. Chua T, Kiat H, Germano G, et al: Gated technetium-99m sestamibi for simultaneous assessment of stress myocardial perfusion, post-exercise regional ventricular function and myocardial viability. J Am Coll Cardiol 23:1107-1114, 1994.

21. Germano G, Kiat H, Kavanagh PB, et al: Automatic quantification of ejection fraction from gated myocardial perfusion SPECT. J Nucl Med 36:2138-2147, 1995.

22. Mock MB, Ringvist I, Fisher LD, et al, and Participants of CASS: Survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation 66:562-568, 1982.

23. Palmas W, Friedman JD, Diamond GA, et al: Incremental value of simultaneous assessment of myocardial function and perfusion with technetium-99m-sestamibi for prediction of extent of coronary artery disease. J Am Coll Cardiol 25:1024-1031, 1995.

24. Borges-Neto S, Shaw LJ, Kesler KL, et al: Prediction of severe coronary artery disease by combined rest and exercise radionuclide angiocardiography and tomographic perfusion imaging with technetium 99m-labeled sestamibi: A comparison with clinical and electrocardiographic data. J Nucl Cardiol 4:189-194, 1997.

25. DePuey EG, Rozanski A: Using gated technetium-99m-sestamibi SPECT to characterize fixed myocardial defects as infarct or artifact. J Nucl Med 36:952-955, 1995.

Dr. Hanson is Chief of Nuclear Cardiology, Assistant Professor of Radiology, and Assistant Professor of Internal Medicine at Duke University Medical Center in Durham, NC.