first-pass radionuclide angiocardiography with single-crystal gamma cameras

First-pass radionuclide angiocardiography with single-crystal gamma cameras

Kenneth Nichols, PhD, E. Gordon DePuey, MD, and Alan Rozanski, MD

Both multicrystal and single-crystal detectors have been in use for more than 25 years for measurement of ejection fraction by analysis of images collected during the first-pass transit of radionuclides through the heart. Originally, multicrystal cameras were preferred, because they provided higher count rates than Anger cameras; however, over the years improvements in count rate capability and collimator design have enabled Anger cameras to perform equally well. This has become an important issue now that readily available 99mTc agents, such as sestamibi, enable evaluation of both myocardial function and perfusion from a single injection. The technical abilities of a particular camera determine which acquisition protocols are most likely to provide clinically useable images for the widest spectrum of patients. Electrocardio- graphic-gated list mode collection is highly desirable for first-pass imaging, providing the greatest flexibility of data review, rebinning, and analysis. Attention to quality control issues of data characterization and processing is important to ensure accuracy and precision of all measurements. Accurate determinations of ejection fraction of the left ventricle are possible routinely and, under favorable circumstances, of the right ventricle as well. (J Nucl Cardiol 1997;4:61-73.)

Key Words: Anger Cameras. first pass • ejection fraction • count rate analysis- radionuclide imaging

Because of the well-established clinical importance of ejection fraction (EF), l 4 the need to obtain accurate, reproducible left ventricular (LV) EF values at rest and during stress has been widely accepted. Since 1963, one means of obtaining this information has been through imaging the first-pass transit of a radionuclide bolus as it traverses the heart chambers. Accomplished originally with special-purpose multicrystal cameras, 5 first-pass techniques advanced rapidly in technical sophistication and became widely adopted. 6

Originally, first-pass imaging was usually performed with 99mTc-labeled blood cells, 99mTc-labeled diethylenetriaminepentaacetic acid (DTPA), or 99mTc- labeled sulfur colloid. Feasibility was also demonstrated for first-pass imaging with other isotopes with short half-lives such as 191mIr, 7'8 195mAu,9 81mKr,I°-14

and 133Xe. I5 These provided high count rates with minimal radiation dose and permitted serial data

From the Department of Radiology and the Division of Cardiology, St. Luke's-Roosevelt Hospital, and Columbia University College of Physicians and Surgeons, New York, N.Y.

Supported in part by a grant from General Electric Medical Systems, Inc.

Reprint requests: Kenneth Nichols, PhD, Division of Cardiology, St.Luke's-Roosevelt Hospital, Amsterdam Ave. at t 14th St., New York, NY 10025.

Copyright © 1997 by American Society of Nuclear Cardiology. 1071-3581/97/$5.00+0 43/72/77795

acquisitions but never gained broad currency and are not now widely employed. 16 With the introduction of 99mTc-labeled sestamibi, for which an activity of 555 MBq to 1.11 GBq (15 to 30 mCi) is injected, it became possible to assess both ventricular function by imaging the first pass of the tracer and myocardial perfusion by conventional single-photon emission computed tomographic (SPECT) imaging. 17

Several studies suggesting the added utility of com- bining perfusion and functional information have been reported with both multicrystal and single-crystal cameras. 18-2° This capability may be especially valuable in evaluating patients suspected of having coronary artery disease 2~ and is presently an area of investigation requir- ing further clinical studies. Hence, there is heightened interest in the ability to asses both LV function and perfusion from a single injection with a single Anger camera, because use of a separate multicrystal camera to obtain functional information is prohibitive for many institutions.

Single-crystal Anger cameras 22 also have been used for first-pass imaging since 1969. 23 However, by the mid-1970s, Anger camera maximum count rate re- sponses were still on the order of only 80 kcps compared with 250 kcps for multicrystal cameras. ~4 It was often impossible to acquire enough counts with Anger cameras to compute LV EF with sufficient accuracyY Therefore

61

62 Nichols et al. Journal of Nuclear Cardiology First-pass radionuclide angiography January/February 1997, Part 1

the majority of first-pass nuclear cardiac imaging has been performed on multicrystal gamma cameras.

Developments in Anger camera electronics in the 1980s improved the count rate capacity of these devices. Rather than generate an analog signal to be exported for further processing, photomultiplier tubes were designed that internally digitized the (x,y) location of detected gamma rays, 26 permitting special-purpose array processors to compute gamma ray location and correct for nonuniform response among the tubesY The outcome of these innovations was an Anger camera with reported 20% count rate loss for input counts of 185 kcps. 28 At about the same time, other array processors were spe- cially designed to improve spatial resolution by compen- sating for Compton scatter. 29 Further advances occurred through detailed pulse shape analysis to correct for multiple-puise overlap, thereby decreasing camera dead time and producing Anger camera maximum count rates of 300 to 600 k c p s , 3°'31 compared with 1 mcp for multiple-crystal gamma cameras. 32,33 The best reported intrinsic spatial resolution of 2.7 mm, achieved by accounting for the depth of interaction of gamma rays within the NaI(T1) crystal, 34 has been accomplished while still providing maximum count rates of greater than 200 kcpsY Recently it has also been shown that by merely replacing the electronics of an older gamma camera with a standard personal computer, to circumvent circuits that divide information on spatial location for energy reregistration, maximum count rates in excess of 200 kcps are possible? 6

Given this evolutionary history of Anger camera count rates, a laboratory with equipment purchased from different companies during different years may have cameras with a considerable range of count rate capabil- ities, some of which are better suited to first-pass imaging than others. Even among Anger cameras man- ufactured in 1996, there is a range of maximum count rates reported by the manufacturers from 100 to 500 kcps, with most new machines rated at greater than 200 kcpsY Thus most new single-crystal gamma cameras provide count rates comparable to those of the first generation of multicrystal detectors.

To exploit further the increased count rates afforded by faster electronics, low-energy ultra-high-sensitivity (LEUHS) collimators have been fashioned for acquisition of first-pass cardiac images to provide EFs in agreement with both gated equilibrium and multicrystal camera first- pass EFs. 31 Multidetector Anger cameras enable rapid and efficient tomographic acquisitions 37 and, when used for biplane first-pass imaging, improve assessment of three- dimensional regional wall motion through depiction of anterior and inferior walls from the right anterior oblique projection simultaneously with portrayal of septal and lateral walls from the left anterior oblique view. 3~

Count Rate Technology

Improvements in the electronic circuitry used in Anger cameras have resulted in increasingly higher count rate abilities. The largest contribution to Anger camera dead time is due to the positioning circuitry that computes gamma ray origin from the relative amounts of current flowing in neighboring photomultiplier t u b e s . 39

Therefore by decreasing dead time, manufacturers have paid the most attention to accelerating the position logic circuits. Dead time is the amount of time needed for an imaging system to recover from detection of a gamma ray to process the next event. Measuring the dead time properties of a system is not difficult and can be accomplished by any of several techniques. Currently the National Electrical Manufacturer's Association recom- mends the "decaying source method" to measure the count rate for a 20% count loss and the camera's maximum count rate, both with and without scatter. 4° It is advisable to measure such parameters for a new camera during acceptance testing to know if it is adequate for first-pass imaging. 4~ Even two gamma cameras of the same model produced within the same year can vary somewhat in their performance characteristics.

The degree to which a camera is partially paralyzed for an individual patient study can be determined by imaging an external radioactive reference source placed on the collimator before injection. As the bolus enters the field of view, the percent decrease of the camera response can thus be measured by observing the percent decrease in reference counts (Figure 1). Counts of the entire frame can then be artificially inflated in an attempt to compensate for partial camera paralysis. 4a However, this technique is useful only if count rate loss magnitude is not excessive, and ideally the maximum percent decrease in camera counting response should not exceed 25% to 30% during the LV phase.

Adequate count rates are of paramount importance. The precision and accuracy with which it is possible to measure EF is highly dependent on count ra te . 43-45

Beyond the question of the statistical uncertainty of counts depicting the ventricular blood pools is the question of the ability of either automated s o f t w a r e 46 o r

visual analysis to identify endocardial boundaries and valve planes and of an observer to judge the success of such choices.

Collimator Design

In conjunction with improved circuit speed, manufacturers have pursued more innovative collimator design to increase collected counts. Of course, designing a collimator that will admit more gamma rays for higher sensitivity is always accompanied by degraded spatial resolution. Allowing too great a gamma ray flux to reach

Journal of Nuclear Cardiology Nichols et al. 63 Volume 4, Number 1;61-73 First-pass radionuclide angiography

Collimator Line Spread Functions Tc-99m with 10cm scatter

0) . 2

0) r e

Figure 1. External reference source method for measuring camera paralyzation for individual clinical study. Single 25 msec right anterior oblique 30-degree frame during LV phase is in upper left, showing marker source placed well below heart. Also displayed are curves through superior vena cava (SVC) (upper right), over left ventricle (lower left), and for marker source (lower right). Note that during LV phase at 10 seconds, marker curve is level but depressed to 60% of original maximum value.

0 4 8 12 16 20 24 28 32 36 40 44

Distance (cm)

UHSENS --HSENS - - LEAP

Figure 2. Line spread functions for three collimators. Low- energy general purpose (LEGP), ordinary low-energy high- sensitivity (LEHS), and low-energy ultra-high-sensitivity (LEUHS) line source count profiles are normalized to same maximum value of 100% and plotted versus distance in millimeters from origin. (From Nichols K, DePuey EG, Goon- eratne N, Salensky H, Friedman M, Cochoff S. First pass ventricular ejection fraction using a single crystal nuclear camera. J Nucl Meal 1994;35:1292-300. Reprinted by permission of the Society of Nuclear Medicine.)

the crystal becomes self-defeating, because exceeding the count rate capacity of a system will only further degrade resolution while altering energy-peaking properties of the camera. In extreme cases this can paralyze the system, thereby resulting in no counts available for forming an image. 4v Opening the energy window to include more gamma rays only exacerbates the effective dead-time paralysis. 4a Collimator design therefore in- volves balancing these competing factors. It is possible to attempt this only for the average imaging situation; however, ultimately too few counts may still be acquired for some individual patient studies.

In designing a collimator for optimal response, the most relevant parameters that can be manipulated are (1) hole area, (2) hole and septal shapes, (3) collimator depth, (4) septal thickness, and (5) septal composition. LEUHS collimators differ from low-energy general- purpose collimators primarily in the ratio of hole diameter/channel depth (Table 1). The improvement in sensitivity of an LEUHS collimator over a low-energy general-purpose collimator of four to five times is accompanied by degradation in system resolution by a factor of 2.0, as measured by the clinically relevant parameter of full width at half maximum of a line source 10 cm from the collimator face with intervening scatter- ing material (Figure 2). It is possible for relative shapes

Table 1. Collimator characteristics

Collimator LEGP LEHS LEUHS

System resolution at 10 cm 9.6 13.8 18.4 with scarer (mm)

Efficiency 0.000213 0.0013491 0.000962 Relative sensitivity (%) 1.0 2.3 4.7 cts/min/ixCi 335 700 1575 Hole diameter (ram) Z.5 3.4 4.6 Septal thickness (ram) 0.3 0.5 0.65 Hole length (mm) 41 36 36

of collimators' line spread function to be similar, with no excessive elongation of line spread function "tails," as indicated by the ratio of full width at tenth maximum values also being 2.0 for an LEUHS collimator compared with a low-energy general-purpose collimator (Figure 2).

In using an LEUHS rather than a low-energy general-purpose collimator, energy resolution can degrade slightly as a result of more Compton-scattered gamma rays reaching the crystal, because the angle of acceptance for LEUHS collimators is larger than for less sensitive collimators. It is advisable to follow individual manufac-


turer's recommendations as to which collimator to use with a given detector to acquire first-pass data. Ideally, these recommendations should be supported by scientific publications reporting EF correlations.

Data Acquisition

Resting Data Acquisition. For global resting LV EF, patients may be imaged with 99rnTc labeled with a choice of different agents. Patients may be injected intravenously with a bolus of 740 to 925 MBq (20 to 25 mCi) 99mTc-labeled red blood cells labeled by either the modified in vivo method 49 or, for higher bonding efficiency, the in vitro technique. 5°-52

Alternatively, patients may receive a bolus of 814 to 925 MBq (22 to 25 mCi) 99mTc-labeled DTPA. s3 Increas- ingly, patients undergoing rest/stress myocardial perfusion analyses such as with 99mTc-labeled sestamibi will receive either 1.11 to 1.15 GBq (30 to 31 mCi) injected during the stress test, acquired 30 to 60 minutes there- after in a resting state, or 740 to 814 MBq (20 to 22 mCi) injected during either the rest or stress portion of a separate-day protocol. 37 With these levels of injected 99mTc-labeled sestamibi, average maximum count rates of 170 kcts have been observed in a group of 31 patients with a biplane single-crystal gamma camera. 46

Boluses can be delivered into the right antecubital vein as rapidly as feasible through 18-gauge indwelling intravenous catheters, pushed by a 20 to 30 ml saline flush, or through the external jugular vein with a 20- gauge needle. 54 The "retrograde" injection method may be useful, as well as use of a stopcock to allow input from two ports. 33

A 30% energy window centered on 140 keV is usually selected. For single-detector Anger cameras, first-pass data are acquired in the right anterior oblique 30-degree projection as either 32 × 32 or 64 × 64 matrixes for 1000 to 1200 frames for 30 seconds, preferably by LEUHS collimation. Usually, 50 msec per frame provides adequate temporal samplingY The advantage of the higher resolution matrix is, given sufficient counts, to facilitate visualization of the valve plane. Advantages of the lower resolution matrix are higher counts for sampling the lung frames for subsequent background correction and providing better temporal resolution of the resultant LV volume curve. Matrixes collected as 32 × 32 have long been used and provide adequate data sampling. 56 It may be most efficient, then, to acquire gated list mode data, because the original collection may be displayed as either 32 × 32 or 64 × 64 matrixes. R wave trigger information should be acquired simultaneously with the images. 57-59

Stress Data Acquisition. For stress imaging, the major differences are related to the fact that the interval

during which the bolus is localized in the left ventricle may correspond to as few as two to three heart beats of a rapidly beating heart. For the right ventricle, it may consist of only one heart beat. Consequently, 50 msec frames will often be too prolonged to sample the ventricular phase adequately, and 30 seconds would be an unnecessarily long imaging time. Therefore stress first- pass frame times should not exceed 25 msec, and acquisition will only rarely require more than 20 sec- ondsY

The manner in which stress testing is accomplished will dictate whether the patient is imaged supine, as with pharmacologic stimulation, semisupine, as on a tilting table equipped with a bicycle, or upright, as seated on a conventional bicycle. If resting first-pass studies are to be acquired in conjunction with stress data collection, these should be performed with the patient in the same position to eliminate differences attributable solely to positioning. Mixing patient acquisition stress testing imaging modes is inadvisable, because although some studies have found that both global and regional LV EF are the same when assessed by treadmill first-pass or bicycle gated equilibrium, 19,6° other reports suggest that regional wall motion assessment may differ, al

For physiologic reasons there should be an advantage to first-pass peak exercise testing over gated equilibrium serial acquisitions. When patients exercise to a peak heart rate, which cannot be sustained with gated equilibrium exercise, there may be a tendency to decrease the workload so as to provide a full 2 minutes of data acquisition during maximum exercise. However, studies indicate that LV EF and wall motion abnormal- ities induced during exercise can recover rapidly after exercise, 6a,63 and this "rebound" can occur even with partial reductions in the workload. First-pass imaging overcomes this particular technical difficulty.

Because patients may move during first-pass data acquisition at peak stress, it may be necessary to detect and correct for patient motion for some individuals. Motion-correction techniques have been developed for multicrystal cameras and generally require the use of a marker source attached to the patient's chest, 19,59,64-66 but these methods have yet to be implemented for Anger cameras. Because these techniques can lead to overesti- mation of LV chamber volume, and because of technical difficulties, bicycle exercise is deemed preferable to treadmill exercise for first-pass stress imaging. 59

These considerations also influence the view in which data should be acquired. Depending on whether the camera is a single- or multiple-detector Anger camera, stress data collection may be achieved more reliably in the anterior, right anterior oblique 45-degree, or right anterior oblique 30-degree views. If a single-detector, small-field-of-view device is to be used with an esti-


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mated degree of caudal tilt, left anterior oblique 45- degree data collection may succeed in separating the chambers. If fusion is to be attempted between the radionuclide images and other modalities such as digital x-ray contrast ventriculograms, the images should be acquired in the same orientations.

Sometimes a small amount of blood pool tracer is injected to aid in patient positioning. This may be helpful if the patient is unusually large, or has an enlarged heart, or if the detector is small (<30 cm). Alternatively, a 185 to 370 MBq (5 to 10 mCi) 57Co flood source may be used as a transmission source to aid in patient positioning. For laboratories that employ reference point sources in the field of view, it is important to ensure that these do not overlie the heart.

Gated List Mode . Gated list mode acquisition is the most complete data collection option, because it records the (x,y) gamma ray locations of each photon detected, timing markers, and R wave triggers all as individual bits of a single 16-bit or 32-bit word for each millisecond 2~ (Figure 3). The use of gated list mode acquisition for first-pass studies is particularly important for Anger camera acquisitions compared with multicrystal devices. There are usually sufficient counts in a multicrystal camera's LV curve so that statistical noise rarely defeats identification of end diastole and end systole from the curve alone. However, for the smaller numbers of counts acquired by single-crystal cameras, gated list mode allows independent R wave identification of end-diastolic and end-systolic times. This timing information is then combined with counts received to sum synchronously the acquired data to produce "representative cycles" of heart contraction. ~6 In cases of less than desirable count rates, some investigators have im- posed a sinusoidal fit to ventricular time-activity

c u I v e s . 67 However, this is inadvisable if it is at all possible to obtain independent R waves. For a low-count study, this can potentially result in blurring the depiction of end-diastolic and end-systolic frames, a disagreeable situation because it could result in incorrectly reduced EF.

With gated list mode data, it is possible to reformat any part of the data as static or dynamic frames, reexamine any time span in detail, subgroup time se- quences according to heart rate, and reformat selected parts of the study as gated synchronous files. Specifi- cally, it allows the user to scrutinize each heart beat of the ventricular phase and discard preventricular contrac- tions. Once the beginning and ending times of the LV phase have been identified, "forward gating" is used to form representative cycles of the beating heart added synchronously after each R wave detected. 16 This is the most widely employed method of producing the equiv- alent dynamic data set analogous to a gated equilibrium study, generating the most faithful representation of the end-diastolic image immediately after detection of the R wave. List mode data collection also allows "backward gating" to add images together synchronously before each R wave, used to produce the most accurate image representation of the diastolic filling phase of the left ventricle.

Quality Control

Although attempts have been made to automate many of the steps involved in reducing first-pass image data, it remains necessary to review the data directly. This provides the observer with an appreciation of image quality, adequacy of counts, bolus integrity, involvement of lung disease, differentiation of cardiac chambers, and

66 Nichols et al. Journal of Nuclear Cardiology First-pass radionuclide angiography January/Febrnary 1997, Part 1

Figure 4. Bolus curve and transit time result. Upper left depicts rectangular region over superior vena cava, superimposed on summed image for entire data acquisition. First 10 seconds of associated time-activity curve is displayed at bottom, and computed transit time is reported in upper right.

an initial impression of global and regional ventricular function. Suitability of the field of view must be verified to ensure the superior vena cava, lungs, and entire ventricles have been included in the field of view, or neither can the quality-control parameters described below be checked nor can adequate ventricular sampling be accomplished for computations of EF.

As described previously, marker sources sometimes are used to aid in the evaluation of count rate dead time. However, if not corrected for, these sources may com- plicate visual appreciation of the cardiovascular aspect of the data by falsely altering count rate maxima and the appearance of overlying structures. If they are superimposed on regions of interest defined for the superior vena cava, lung, or ventricle and are not compensated f o r correctly, they will invalidate any numeric measurements derived from counts within those regions. Likewise, failure to account for extraneous reference sources can confound software designed to automate data processing with total frame count-density information.

The most pivotal quality control parameter for first-pass Anger data is counts collected. For EF precision to exceed 1% to 2%, total background-corrected ventricular counts in the end-diastolic frame of the representative cycle must exceed 2000 counts. 68 Clinical data acquisitions with currently available Anger cameras have verified that this minimum requirement can be achieved. 31,65,69 If EF were computed from end-diastolic and end-systolic counts alone, 2000 end-diastolic counts would give an EF error of 2% for EF = 50%, based on

Poisson statistics. Correspondingly, computer simula- tions have demonstrated that EF derived from Fourier- fitted curves of 12 to 36 points per R-R interval, for which end-diastolic counts ranged from 1500 to 3000 counts, had a resulting EF error of 1% to 2%. 45

It is important to characterize the bolus shape, because an extended or fractionated bolus can result in excessive lung counts during the LV phase and thereby oversubtraction of subsequent LV images so that EF is too high. Reasons for an inadequate bolus include suboptimal injection technique (such as failure to follow the tracer with a rapid saline flush) and Valsalva maneu- ver by the patient. The bolus is generally sampled in a small region over the superior vena cava and should have a discrete, single-peaked appearance. Either the transit time or full width at half maximum of this curve is computed and routinely reported as part of the quality control. For these purposes, this curve is usually fit to a gamma variate form for the first 10 seconds of data, or before appearance of significant lung counts 2s (Figure 4). Transit times should ideally be less than 1 1/2 seconds and never more than 2 seconds for a resting study, or the study may not be reliable for computation of global LV EF.

Lung transit time is assessed to verify that the bolus both exited the fight ventricle and cleared the lungs rapidly. Reasons this can fail despite a "tight" input bolus are right-sided heart valvular disease, pulmonary hyper- tension, primary lung disease, and early recirculation associated with shunting. 7° Any of these conditions can extend the bolus entering the left ventricle, resulting in excessive lung counts during the LV phase. These conditions are sometimes associated, because severe lung disease is a frequent finding simultaneous with reduced fight ventricular EF. 53

A region is placed over the fight lung for LV EF studies, and it is often useful to view this region simultaneously superimposed on the summed image of the entire study, to ensure that the lung region does not overlie the heart or great vessels. A gamma variate fit is usually applied to the lung curve 71 (Figure 5). As with the bolus curve, either the full width at half maximum or the transit time is reported as part of routine first-pass quality control. Lung transit is usually expressed in units of heart beats and ideally should be less than eight, and never exceed 10, heart beats 71 or LV EF will be incorrectly high, as described above.

The next quality control check is to determine whether the separately recorded R wave triggers match local count maxima of a curve generated from a region approximating the left ventricle during the LV phase of the study (Figure 6). Because the LV phase rarely encompasses more than eight to 10 heart beats, arrhyth- mias can invalidate the study. 16 Other reasons for being


Figure 5. Lung curve and transit time result. Upper left depicts irregular region over vicinity of lung as seen on summed image. First 30 seconds of associated time-activity curve is displayed at bottom left, with gamma variate-fitted curve on lower right, and computed transit time is reported in upper right.

unable to use the R waves include inadequate patient skin preparation or ineffectual electrode placement, resulting in an inadequate electrocardiographic signal and erroneous electronic delays between the heart monitor and the gamma camera's computer. In the absence of these triggers, or if they do not coincide with count maxima, it may not be possible to construct a reframed representative heart cycle accurately, particularly for a low-count curve characterized by a low signal/noise ratio in conjunction with low EF (<25%).

Left Ventricular Ejection Fraction

Computation of EF has been done either from the analysis of time-activity curves generated beneath a region isolating the ventricle 56,72-74 or by analyzing images refrained as if a gated equilibrium study had been acquired for the period during which activity is localized in the ventricle. 57,75,76 Increasingly, the final EF measurement relies on steps employed in both methods, which formerly were two distinct approaches. Regardless of the method used, reframing is usually necessary for an observer to review the data and provide computer algo- rithms with optimum input data.

Typically, once the entire first-pass study is acquired, images are reframed at 0.1 second. Bolus and lung quality control is performed as described above, followed by initial drawing of an approximate LV region. Then the time-activity curve is generated for that

Figure 6. R waves match LV count peaks. On graph at top, independently recorded R wave triggers are displayed as vertical lines intersecting time-activity curve for region approximating left ventricle. Heart beats automatically accepted by computer algorithm are indicated on curve by hatch marks and are reported in table at lower right. Lung time marker is shown on left of curve coincident with curve minimum, along with "lung frame image" during time displayed at lower left.

region, from which beginning and end times for the LV phase and acceptable heart beats are determined.

Two background correction data processing options are most common. Correction for background counts is performed by either subtracting counts of a paraventricular region defined by the operator (Figure 7) or a "lung frame method ''69,77 of removing counts to varying de- grees throughout the LV phase of the study based on the observance of lung counts before and during the LV phase (Figure 8). For each of the background methods, data are analyzed further as to whether L ¥ counts were taken from a single end-diastolic region or separate end-diastolic and end-systolic regions. It has been shown that the lung frame correction method is the more reliable of the two for first-pass data, which in conjunction with the use of separate end-diastolic and end- systolic outlines produced results best in agreement with gated equilibrium EF values? 1 Use of this technique requires identifying a particular point in time for a representative lung frame. In some approaches this is taken as the minimum of the whole-frame data density curve between the right ventricular and LV count peaks. 7s

The phase of the study encompassing the appearance of activity in the left ventricle until the tracer arrives in the aorta is then refined. Fourier analysis is often employed to discriminate the chambers and identify the LV

68 Nichols et al. Journal of Nuclear Cardiology First-pass radionuclide angiography Jaamary/February 1997, Part 1

Figure 7. Paraventricular lung region for background correction. Manually drawn region is drawn along arc from 3 o'clock to 6 o'clock position beyond left ventricle as seen in right anterior oblique (RAO) 30-degree view to sample lung vicinity for estimated background count correction.

Figure 9. Fourier phase images to assist in LV localization. End-diastolic (ED) frame of representative cycle for time span approximating LV phase is shown at upper left, with end systole (ES) at upper right. First harmonic Fourier phase image (lower left) is used to define valve plane between LV region (purple) and outflow tract (yellow). Same LV region is shown superimposed on Fourier amplitude image (lower left) and end-diastolic and end-systolic images.

Figure 8. Lung frame method of background correction. Twenty-five msec frames of original data are shown for peak LV phase (upper left) and peak lung phase (upper right). Lung frame is then used in conjunction with sampled lung counts versus time to correct all images by different proportions over time during LV phase, as shown on lower left. LV images are then filtered spatially (lower right).

boundary. 69 The depiction of the results is commonly shown in color to emphasize the phase separation 79 (Figure 9). The two-dimensional phase image provides the most consistent means of identifying the valve plane

separating the LV from the aortic outflow tract 8° and works well even when the LV phase pattern itself is markedly abnormal. The two-dimensional amplitude may help verify the extent of the left ventricle, but the LV image itself is normally used for delineating the LV boundary beyond the valve plane.

The LV region is then used to produce a refined time-activity curve for the LV phase. If R wave triggers are coincident with count rate peaks, the average heart rate during this time segment can be computed and shorter or longer heart beats discarded. A heart beat acceptance window of 20% of the mean is often used. In case of low count rates, it may be possible to include more beats for greater total LV counts but only if it is observed that nearly identical LV EF results are obtained regardless of the number of cycles included. Accepted heart beats can be used then to identify the time markers of the original gated list mode data needed to form a representative heart cycle for improved LV depiction. A final LV image and time-activity curve are produced for evaluation of EF and related curve parameters (Figure 10), such as peak filling rate, time to peak filling, 81 and filling fraction, s2 Usually these parameters are derived not from the EF curve itself but rather from a Fourier fit of the curve to a third-order series of harmonic functions.44'45,83-85

Several of the image-processing steps have been


automated, according to an expert systems approach. 46 These include (1) generation of superior vena caval and lung regions for quality control; (2) initial and iterative LV outlines; and (3) choices of beginning and ending times for analysis of superior vena caval, lung, and representative cycle ventricular count curves. This has been accomplished partly by analysis of the data density curve, which is the maximum count per pixel in the entire frame plotted versus time. 7a At the point of determining the best LV region, some programs have been designed to iterate between increasingly refined LV drawings to generate further refined time-activity curves, which may produce a better estimate of correct accepted heart cycles. At some point, of course, a final LV image and time-activity curve must be produced.

Some success in automating first-pass data processing has been reported with "eigenimage" filters. 86 This technique is an extension of factor analysis of time- activity curves of each pixel in a time-varying image series, as employed successfully for the automated iso- lation of the left ventricle in planar gated blood studies. 87 The net effect of this approach is to remove counts from the lung, non-LV portions of the heart, and background that interfere at different times with different subregions of the left ventricle, thereby leaving only images com- prised of pure LV counts. Although computer simula- tions indicate this technique to have potential in improv- ing accuracy of EF and precision for first-pass data of high noise/signal ratio, 86 further clinical studies are needed to verify its efficacy.

Right Ventricular Ejection Fraction

The diagnosis of several pathologic conditions can be aided by knowledge of right ventricular EF alone or in combination with knowledge of LV EF. 53,88 Under favorable circumstances, valid right ventricular EF evaluations are possible. However, because it is difficult to know whether injected tracer is sufficiently well mixed with blood in the right ventricular phase, accuracy of right ventricular EF computations can be suspect, even under ideal conditions of average flow rates and unam- biguous depiction of valve planes. For this reason it may be advisable to inject the tracer bolus more slowly if right ventricular function specifically is to be evaluated.

Gated first-pass data processing for right ventricular EF is similar to that for LV EF processing, s9 The main difference is in identification of the tricuspid valve, which can translate considerably during the heart cycle. 9°,91 Frequently there is little background to contend with in right ventricular studies, because the lungs should not yet be filled with tracer. 92 If lung background is present, techniques have been described that can compensate for t h i s , 93 the most frequently employed method

Figure 10. LV volume curve. Count rates of original data collected are sampled during accepted heart beat intervals separately for end-diastolic (ED) and end-systolic (ES) periods and then interpolated in time and fit to third-order harmonic series, to generate LV volume curve (upper right) from which EF is computed. Associated curve parameters and relevant patient information are reported beneath curve.

being use of a crescent-shaped region adjacent to the right ventricle? 3 It is important for the observer to verify that the few (three to five) heart beats are of average duration for the patient. Because the radioactivity con- centration is higher for the right ventricular phase than for the LV phase, only a few accepted heart beats may yield adequate counts when added synchronously to form a representative cycle 94 (Figure 11).

Visual Analysis

Part of first-pass imaging is just the visual analysis of ventricular size and shape and global and regional motion. Abnormally large ventricular size may indicate any of several possible pathologic conditions. 6 True or false aneurysms may be appreciated from first-pass images. The representative cycle images for the LV phase of the study usually are filtered spatially to provide image quality suitable for visual evaluation of regional wall motion. In addition, segmental EFs are often computed from the final LV region and representative cycle images. For right anterior oblique 30-degree LV data, the regional segments are frequently divided into infero- basal, inferoapical, apical, anteroapical, and anterobasal territories of equal angles. The final display of results usually includes cinematic playback loops of the representative cycles, synchronously for both views if biplane first-pass data have been acquired.


Figure 11. R waves match right ventricular (RV) count peaks. Approximate region to sample right ventricular counts a long with one 25 msec frame during right ventricular phase of study is shown on lower left, with associated time-activity curve and independent R wave markers shown above. Algorithm automatically identified only two heart beats corresponding to counts above 70% of curve maximum.

Ejection Fraction Validations

Studies comparing Anger camera first-pass LV EF to gated equilibrium values have demonstrated correlation coefficients from linear regression analysis of r = 0.89 (n = 19), 95 r = 0.91 (n = 17), 90 and r = 0.92 (n = 28) . 31 Earlier studies (1984) comparing Anger camera to multicrystal camera first-pass LV EF demonstrated linear correlation of r = 0.83 (n = 135 ) , 43 but improvements in camera technology and data processing techniques sub- sequently produced higher correlations of r = 0.94 (n = 26) in 199196 and r -- 0.94 (n = 28) in 1994. 31 Thus linear correlations reflective of r = 0.94 would be expected currently. Likewise, studies of interobserver variability have yielded similar correlation coefficients .31.43,46.69

For biplane gamma cameras, LV EF curves can be generated from both the right anterior oblique and left anterior views. However, global EFs computed from data acquired in the left anterior oblique projection consis- tently underestimate global EFs computed from right anterior oblique images, and left anterior oblique 60- degree regional EFs are less reliable for the upper half of the heart? 8 The reason for this is that, although the right anterior oblique 30-degree view separates the left atrium from the left ventricle, the orthogonal left anterior oblique 60-degree projection usually does not. In addition, there is no reason to use caudal tilt for right anterior oblique images, in the absence of which the left atrium is even less likely to be distinguishable from the left

ventricle in the left anterior oblique projection. Conse- quently, left anterior oblique biplane first-pass images are processed solely to provide an impression of lateral and septal regional wall motion from the left anterior oblique view simultaneously with the anterior and inferior regional wall motion seen in the right anterior oblique projection. 3s

Under favorable circumstances, it is possible to obtain highly reproducible right ventricular EFs that agree well with gated first-pass analyses. 58,97 However, even in normal patients the right ventricle is an eccen- trically shaped structure "wrapping around" the left ventricle. The variability of right ventricular shapes is great, as is the variation in the position of the right atrium with respect to the right ventricle. Thus even though judicious choice of azimuthal and caudal angles can usually be found that separate the right from left ventricular chambers, and the left atrium from the left ventricle, it is often difficult to distinguish the right atrium from the right ventricle and to identify the pulmonary valve plane. 33,8s Consequently, measurements of right ventricular EF may not be possible in individual patient studies.

Therefore it is not surprising that some studies comparing first-pass with equilibrium right ventricular EF measurements have found a range of linear regression analysis correlation coefficients from r = 0.28 (n = 135) 43 to r = 0.78 (n = 15). 96 Comparison of first-pass right ventricular EF with x-ray contrast angiography has demonstrated r = 0.60 (n = 33). 96 These findings may be more indicative of the inadequacy of gated equilibrium studies or contrast angiography for right ventricular EF than an indictment of first-pass right ventricular EF, because comparisons of first-pass to cine computed tomographic scanning have demonstrated excellent agreement (r = 0.96; n = 29) but relatively poorer agreement (r -- 0.71; n = 27) between equilibrium right ventricular EF and cine computed tomographic right ventricular EF. 9° Comparison of single-crystal right ventricular EF with multicrystal evaluations demonstrated a range of values of r = 0.69 to r = 0.81 (n = 19) for different observers performing the calculations, 31 most likely because of greater difficulty in identifying the valve plane and temporally isolating the time phase defining peak ventricular filling of the right ventricular phase compared with the LV phase. Other investigators have reported better success (r = 0.97; n = 21) in comparing right ventricular EF by single-crystal gated first-pass compared with multicrystal first-pass imaging. 94

Summary

First-pass radionuclide imaging has a long history. One advantage over other methods is the short amount of

Journal of Nuclear Cardiology Nichols et aL 71 Volume 4, Number 1;61-73 First-pass radionuclide angiography

t ime requ i red for da ta col lec t ion , so r e l i ance on pa t i en t

c o o p e r a t i o n for this t e c h n i q u e can be kep t to a min i -

m u m . 69,98 B e c a u s e o f p r o b l e m s w i th x- ray con t ras t an-

g i o g r a p h y and e q u i l i b r i u m ga ted b l o o d poo l s tudies

(par t icu la r ly for the r igh t vent r ic le ) , m a n y obse rve r s

be l i eve f i rs t -pass t e chn iques p r o v i d e the m o s t accura te

d e t e r m i n a t i o n o f EF. 92

In the past , on ly spec ia l -pu rpose mul t i c rys t a l c am-

eras we re adequa t e for f i rs t -pass r ad ionuc l ide imaging99;

howeve r , n o w s ing le -c rys ta l de tec tors c an p e r f o r m

nea r ly as well . M a x i m u m c o u n t ra tes of m o s t n e w A n g e r

c amera s e x c e e d 200 kcps , w i th some ach i ev ing 350 to

600 kcps , so rou t ine ly a c h i e v i n g the m i n i m u m n e c e s s a r y

2000 b a c k g r o u n d - c o r r e c t e d L V end-d ia s to l i c coun t s is

n o w pract ical . D e t e r m i n a t i o n s o f L V E F wi th A n g e r

c amera s cor re la te h igh ly w i th bo th ga ted equ i l i b r i u m

va lues and E F d e t e r m i n e d f r o m mul t i c ry s t a l g a m m a

cameras . W i t h a u t o m a t e d p r o c e s s i n g 46 o f b ip l ane first-

pass images , 38 it is l ike ly tha t the r eg iona l wal l m o t i o n

and g loba l E F i n f o r m a t i o n o b t a i n e d f rom f i rs t -pass s tud-

ies w i th s ing le -c rys ta l c amera s in c o n j u n c t i o n wi th

99mTc-labeled s e s t amib i p e r f u s i o n t o m o g r a p h y f rom the

s ame c a m e r a wil l p r o v e usefu l in the eva lua t ion of

co rona ry ar tery disease .

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first-pass radionuclide angiocardiography with single-crystal gamma cameras

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