Chapter 11: ECG-Gated SPECT Imaging for Assessment of Ventricular Function and Dyssynchrony

The introduction of electrocardiographic (ECG)-gated myocardial single-photon emission computed tomography (SPECT) in the 1990s expanded the application of myocardial perfusion imaging to routinely include the assessment of LV systolic function.¹ The development and use of this technique occurred when technetium-based imaging agents were placed into clinical use as these tracers provided much higher counts, and therefore image quality for measuring function. This was a critical development in the evolution of myocardial perfusion imaging. Currently, the majority of myocardial perfusion studies performed in the United States use gated SPECT technology and Tc-99m tracers. A more recent development has been the evaluation of ventricular dyssynchrony by SPECT, providing further data beyond myocardial perfusion. This chapter will discuss both aspects of ventricular assessment.

Technical Considerations

Hardware Requirements

Gated SPECT images can be acquired using single- or multiple-detector cameras. More recently, dual-headed cameras in the 90-degree configuration have been preferred, as images can be acquired in half the time required using a single-headed system without sacrificing image quality. The majority of gated SPECT imaging is performed with high-resolution parallel hole collimators for Tc-99m studies, while all-purpose collimators are used for thallium-201 (Tl-201) studies. A 180-degree imaging arc (45-degree right anterior oblique to 45-degree left posterior oblique projections) with a circular orbit is most commonly used, although noncircular (body contour) orbits can also be used. The most common detector rotation mode is the "continuous step and shoot" acquisition method, in which the detector records events when stationary at each projection, and then rotates (moves) to the next projection. A "continuous" acquisition mode is also available. The standard image matrix size for gated and nongated SPECT imaging is 64 × 64 pixels, with pixel sizes of 5 to 7 mm. This size offers adequate image resolution for interpretation and quantitation of both Tl-201 and Tc-99m tomograms. Contemporary computers possess adequate processing speed and internal hard disk space to process and store large amounts of scintigraphic data. Acquisition computers are usually separate from processing computers to allow for efficient laboratory operations. In addition, unsophisticated, relatively inexpensive, three-lead gating devices are provided by manufacturers to supply the trigger to the acquisition computer.²

Gated SPECT Acquisition and Processing

In an ECG-gated acquisition, a three-lead ECG provides the R-wave trigger to the acquisition computer, with two successive R-wave peaks on the ECG defining a cardiac cycle. Counts from each phase of the cardiac cycle are binned to a corresponding temporal "frame" within the computer. Perfusion projection images are obtained from summation of the individual frames (Fig. 11-1).¹ There is a trade-off between the temporal resolution of gated Tc-99m-sestamibi images and the count density of the individual frames. Gating of myocardial perfusion is usually performed at 8 or 16 frames per R–R interval per projection to maintain the count density using a single-headed camera, although 32 frames per cycle are also possible. With dual-headed cameras, 16 frames per cycle (rather than 8 frames) are preferred as the ejection fraction (EF) results are more in line with other imaging modalities. With a multiheaded SPECT system, more frames can be acquired with no increase in acquisition time, as these systems can obtain higher count density images.

Most manufacturers provide one of two modes of gated SPECT acquisition—"fixed" or "variable"—to define the R–R interval. In fixed acquisition mode, the R–R interval is estimated by the acquisition computer prior to the study, based on previously observed 10 to 20 heartbeats, and remains fixed throughout the study. In the variable acquisition mode, the heart rate is continuously monitored throughout the study and the acquisition computer alters the duration of temporal frames as needed to bin counts equally into the prespecified intervals (8 or 16) per each previously detected R–R interval. In both of these modes "fixed" and "variable," the data cannot be reformatted after acquisition is complete. An alternative to this is the list mode, a technique increasingly used in contemporary radionuclide studies.³ This technique allows counts to be reformatted into temporal frames after acquisition is complete. The computer records the spatial coordinates of each detected count as well as the timing marker that identifies at what time the count was detected. After acquisition, gated SPECT frames are generated by selecting the mean R–R interval and the beat rejection criteria followed by appropriate binning of the data. The advantage of the list mode is its flexibility, and thus potentially avoids the gating artifacts seen in the fixed- and the variable-mode acquisitions. A disadvantage, however, is that it requires storage of massive amounts of data, and therefore was rarely used in clinical practice until recently, when high-capacity computers became ubiquitous.²

Variations in heart rate due to a variety of factors (sinus arrhythmia, other arrhythmias, patient anxiety or motion, poor ECG lead contact, etc.) can result in temporal "blurring," that is, mixing of counts from adjacent frames. To limit acquired data to those heartbeats that are representative of the patient's average heartbeat and to minimize temporal blurring, a beat rejection window is set by specifying the acceptable deviation of R–R interval from the expected value. A 20% (±10) window has historically been applied, although in patients with highly variable heart rates, up to a 100% (±50) acceptance window can be set. Some camera manufacturers provide an extra frame in which counts from all rejected beats are accumulated. The counts within the extra frame can be added to the nongated data after the acquisition is complete in order to generate a summed SPECT dataset for interpretation of the static perfusion images. On most commercial systems, a premature ventricular contraction (PVC) mode may be set that programs the computer to skip one or more cardiac beats before the R–R gating is reestablished. This is done to avoid mixing counts from the two successive cardiac cycles.²

As can be inferred from the above discussion, the detection of an adequate R-wave signal is essential to the successful collection of image data synchronized to heart rate. In patients with severe arrhythmias, the triggering mechanism is incapable of properly identifying the R wave and EF fluctuations, artifactual perfusion abnormalities, and wall thickening discordance may occur.³ Thus, in this situation, a nongated SPECT study may be preferred.

A variety of single- and 2-day protocols may be used in conjunction with gated SPECT. As long as counts are adequate, either Tl-201 or Tc-99m perfusion tracers may be used. Either or both the acquisitions composing the stress/rest or rest/stress protocol can be gated, although the most commonly utilized is the high-dose technetium stress study because of its superior count density. Although the common practice is to gate only the poststress image, a study by Johnson et al.⁴ reported that in 36% of patients with reversible perfusion defects, the poststress left ventricular ejection fraction (LVEF) was >5% lower than at rest. This implies that global and regional LV functions obtained from poststress–gated acquisitions are not representative of basal LV function in patients with stress-induced ischemia, and that perhaps both rest and stress images should be gated routinely, as long as count density is adequate. It is currently recommended that both rest and stress ECG gating be performed. In general, resting function is of lesser quality due to lower counts and information is not reported unless changes occur between the post stress and rest images.

The ECG-gated SPECT procedure results in the derivation of a time–volume curve, based on the volume of the left ventricle derived by endocardial definition at each of the 8 or 16 bins (frames) within one cardiac cycle. This is in contrast to the time–activity curve derived from radionuclide ventriculography (RVG), a technique that calculates EF from the difference in LV cavity counts between end-systole and end-diastole, rather than from LV volumes determined by endocardial definition. This technique is reviewed in Chapter 22.

Procedure for Interpretation of ECG-Gated SPECT Imaging

To maximize the value of functional ECG-gated SPECT data, a systematic approach to interpretation is essential. Ventricular function should be interpreted only in the context of the perfusion data, as the latter has potential to influence the results and, the two sets of information are complementary. The sequence of interpretation is listed in Table 11-1, and should begin with the evaluation of rotation images followed by perfusion data and finally ventricular function. The final step is integration of clinical information.

Evaluation of Unprocessed (Raw) Data

The interpretation of gated SPECT begins with evaluation of the rotating unprocessed data for overall image quality and any information that might impact function. This includes potential soft tissue attenuation from breast or diaphragm, and interference from extra cardiac liver or gut activity. Inspection of raw data provides assessment of the technical quality of gated SPECT acquisition. In general, images with poor counts should be interpreted with caution as they could be associated with artifacts. Periodic flashing of the display results from gating errors, occurring as a result of wide variation in the cardiac cycle during the acquisition leading to variation in counts between images. Wide variability of R–R interval can also cause a radial blurring artifact in the gated tomographic images. This may limit the definition of end-systolic frame, affecting LVEF and end-systolic volume (ESV) measurements. The presence of gating errors can be further confirmed by graphs displaying accepted counts as a function of the projection number. If there are no gating errors, all projection curves should superimpose nearly perfectly.

Evaluation of Myocardial Perfusion Data

Tomographic slices of the myocardium should be displayed according to the standardized model recommended by the American Society of Nuclear Cardiology,⁵ and interpreted prior to assessment of ventricular function. Using this model, the myocardium is divided into 17 segments based on three short-axis slices (the apical, mid-ventricular, and basal) and a mid-ventricular vertical long-axis slice. The presence of a defect and the degree of reversibility (differences between stress and rest) should also be noted. Quantitative confirmation of the visual observations of the perfusion data should generally be made. Fixed and reversible perfusion deficits should be carefully evaluated for regional function as described in the next section.

Evaluation of Ventricular Function

Assessment of wall motion should be performed for both the left and the right ventricle. Assessment should include both global left and right ventricular function, and regional function for the left ventricle. The latter is critically important in the presence of a perfusion abnormality. It is generally recommended that ventricular function be interpreted using at least three short-axis slices and one horizontal and vertical long-axis slice at a magnification sufficient to easily assess regional changes. The short-axis slices selected should be similar to those used for perfusion interpretation to enable meaningful comparison.

Assessment of Global Ventricular Function

The interpreter should first estimate the global LVEF by visual interpretation, and then confirm with the quantitative software. Confirmation of quantitated LVEF should include examining the contours, as gut and liver activity might be mistakenly included. It is important for the reader to know the lower limit of normal for a given software quantitation package, since the absolute number varies by imaging modality as well as among software and hardware vendors. Global function can be categorized as normal (EF >50%), mild (EF 40–50%), moderate (EF 30–40%), or severe (EF <30%).

Evaluation of Regional Ventricular Function

Parameters of regional ventricular function assessed by gated SPECT include segmental myocardial wall motion and myocardial thickening. Segmental wall motion analysis consists of observing both epicardial and endocardial surfaces. Wall motion in one region should be compared to adjacent regions (i.e., inferior compared with anterior). In general, wall motion is best observed using monochrome display scales (thermal, gray, etc.), while wall thickening is best observed using color scale (e.g., isocontour). Assessment of both wall motion and wall thickening contributes to overall evaluation of ventricular function. A visual semi-quantitative assessment of regional wall motion and thickening can be performed using the same 17-segment model used for perfusion assessment. For assessing wall motion, a six-point (0, normal; 1, mild hypokinesis; 2, moderate hypokinesis; 3, severe hypokinesis; 4, akinesis; and 5, dyskinesis) scoring system is used.⁵ This includes estimation and quantification of LVEF and quantification of LV volumes. Completely automated algorithms, both count based and geometry based, are available.

Right ventricular (RV) size and global functions should also be noted, and important clinical data points. Reports should reflect the best estimation of RV size and function.

While 8- and 16-bin gating are routinely performed for data acquisition, ASNC guidelines recommend the latter. Recent data demonstrate that a larger number of gating bins results in higher fidelity of the time–volume curve, a fact that has practical implications. First, a 16-bin study routinely results in a higher EF value (by approximately 4–5 EF units) compared to 8-bin gating,⁶ which is more in line with other modalities. In our institution the EF threshold for normality is 45% and 50%, for 8-bin and 16-bin gating, respectively. Second, it is generally accepted that at least 32-bin gating is required for optimal assessment of LV diastolic function, an approach that is generally impractical during SPECT acquisition due to the long acquisition time required.⁷

The assessment of LV systolic function by gated SPECT has undergone an extensive validation.⁸ However, the 50% threshold for normality of EF was derived from RVG.^9,10 It is well established that the absolute EF numbers are not interchangeable between modalities, and that the threshold for normality should really be modality specific.¹¹ Nevertheless, the 50% threshold is applied across modalities for convenience, and the intermodality variability in absolute EF has been ignored even in the design of landmark clinical trials which have recruited patients based on an absolute EF value. For example, in the Multicenter Automatic Defibrillator Implantation (MADIT) trials the inclusion criteria of EF <35% could be determined by "angiography, radionuclide scanning, or echocardiography."¹² Furthermore, this intermodality variability is exaggerated in patients with LV systolic dysfunction.¹³

The clinically important attributes of biological measurements are accuracy and precision (reproducibility and repeatability). In the case of EF measurements, the absence of a truth standard makes accuracy difficult to determine. However, measurements of precision are particularly important for serial assessment, and is a strength of radionuclide-based approaches which are largely automated and rely less on operator input. Reproducibility refers to the serial processing of an acquired dataset by the same or different individual, and reflects the effects of operator input on the technique. Repeatability refers to variability in serial acquisition of the data and its subsequent processing. High reproducibility is therefore an inherent requirement for high repeatability. In the context of LVEF, when serial studies are performed in close temporal proximity (e.g., within minutes of each other), technical variability is measured, whereas studies performed days apart reflect both technical and biological variability.¹⁴ It is important to use the same processing software processing protocol for EF determination as there is considerable variability among vendors.

In general, EF determination by gated SPECT requires less operator input than RVG, unless completely automatic border detection options are chosen for the processing of the latter. However, several factors affect EF determination by SPECT. Equipment and processing software have profound influences and should be kept constant for serial imaging.¹⁵ Patient position, tracer dose, interval between tracer injection and imaging, image reorientation angle, and the presence of large perfusion defects can affect EF determination, often surreptitiously.^16–19 The tracer dose and time to imaging affect the target to background ratio and thus, delineation LV borders and segmentation. Available data suggest that the repeatability coefficients (obtained by Bland Altman plotting) for RVG and gated SPECT for serial LVEF assessment are comparable, and in the range of 6% to 8% (EF units).^14,20 LVEF changes on serial imaging beyond this range generally reflect a true difference. It must be noted that the contractile reserve of a normal LV is much higher (50–85%) than that of a dysfunctional ventricle. Thus biological variability is higher in the normal LV.²¹

As the left ventricle becomes dysfunctional and dilated, count statistics in the LV cavity improve, in contrast to the thinned out LV myocardium. Myocardial count statistics are further compromised by large perfusion defects. Thus, RVG may have some inherent advantages over SPECT myocardial perfusion imaging in the assessment of the dysfunctional left ventricle.

Clinical Uses of Gated SPECT Imaging

There are numerous clinical applications of the gated functional data (Table 11-2). The additive value of functional data to nongated perfusion data has been consistently shown in prior studies.

Differentiating Attenuation Artifacts from Scar

A useful clinical application of gated SPECT imaging is in adjudicating fixed perfusion defects which could be either scar or soft tissue attenuation. The basic assumption using ECG-gated SPECT imaging for this purpose is that a fixed perfusion abnormality associated with CAD should represent either prior myocardial infarction (MI) or stunned myocardium, both of which are associated with wall motion abnormalities. In contrast, if wall motion in the same area as the fixed perfusion abnormality is normal, this should represent attenuation artifact. Thus, a fixed perfusion abnormality with normal wall motion should be considered normal. This interpretation would therefore reduce the number of "false-positive" studies and improve specificity. Several studies have been published,^22,23 demonstrating improved specificity using this assumption (Fig. 11-2).

By incorporating regional wall motion data in the interpretation of perfusion imaging, DePuey and Rozanski²² demonstrated that false-positive perfusion studies could be reduced from 14% to 3%. In patients with low likelihood of CAD, the normalcy rate increased from 74% to 93%. In patients with a high likelihood for CAD, the trend was also toward a higher number of unequivocally abnormal interpretations. In women, where the false-positive rate of stress ECGs is relatively high and breast attenuation artifact common, ECG gating was shown to further enhance the diagnostic specificity of Tc-99m perfusion imaging from 84% to 94%.²³ Subsequently, Smanio et al.²⁴ demonstrated that the addition of gated SPECT for the assessment of regional systolic function reduces the degree of uncertainty in the interpretation of Tc-99m-sestamibi perfusion studies. The numbers of "borderline normal" or "borderline abnormal" interpretations were significantly reduced (Fig. 11-3).

Gated SPECT imaging is limited in distinguishing attenuation artifact in those patients with reversible perfusion abnormalities or those with either stress-only imaging or acute rest myocardial perfusion in the emergency department (ED) with no reference image. In any of these circumstances, if wall motion is normal, one cannot exclude the presence of ischemia as an etiology of the perfusion abnormality. Since ventricular function is assessed 30 to 60 minutes later, any wall motion abnormality created by ischemia would, for the most part, have resolved by the time of imaging. In both ED and stress-only imaging, a reference image must be obtained for comparison. Reversible perfusion abnormalities must be considered abnormal despite normal wall motion.

Enhanced Detection of Coronary Artery Disease

In addition to improving diagnostic specificity, the capability to obtain functional information through gating may also enhance the detection of CAD, particularly multivessel disease. While proven in various studies that SPECT MPI reliably detects CAD, the question of underestimating ischemia in the case of multivessel disease or left main disease because of balanced global hypoperfusion comes into question. Several reports have estimated that only 13% to 50% of patients with three-vessel CAD or left main disease actually have perfusion abnormalities in multiple territories, thus potentially leading clinicians to underestimate risk.^25–27 Several studies have demonstrated the incremental value of utilizing both functional and perfusion data in detecting multivessel disease or high-grade stenoses over perfusion data alone. Sharir et al.²⁸ examined a population of 99 patients who underwent dual-isotope resting Tl-201/exercise-gated Tc-99m-sestamibi SPECT with normal resting perfusion. Multivariate regression analysis suggested that both extensive perfusion abnormalities and the presence of wall motion abnormalities in multiple territories were independent predictors of severe multivessel CAD, but that the addition of wall motion variables to perfusion data resulted in a significant increase in accuracy for predicting severe proximal left anterior descending (LAD) as well as multivessel CAD. For perfusion alone, sensitivity was 49%, while combined perfusion and wall motion abnormality yielded a sensitivity of 82%.

Furthermore, the use of rest and stress LVEF may assist in the detection of multivessel coronary disease, as demonstrated in a study by Yamagishi et al.²⁹ wherein the combination of perfusion data and worsening of the LVEF significantly increased sensitivity in detecting multivessel CAD over Tl-201 perfusion defects or rest LVEF and postexercise LVEF alone (43.3% vs. 26.9%, 25.4%, and 25.4%, respectively). Another study sought to correlate degree of angiographic stenosis with the presence of regional wall motion abnormalities (RWMAs) on exercise stress/rest-gated technetium-99m SPECT studies.³⁰ Reversible RWMAs were found to be highly specific for angiographic stenoses >70%, both overall and for specific vascular territories (94–100%). Furthermore, when patients were stratified according to severity of angiographic stenoses (50–79% and 80–99%), the presence of reversible RWMA distinguished a higher angiographic severity with positive predictive values between 77% and 88% for specific vascular territories.

Prognosis and Risk Stratification

As is the case with perfusion imaging in general, gated SPECT imaging has also found an important role in the risk assessment of patients with known or suspected CAD. This is not surprising, given the well-recognized prognostic role of LV function with regard to long-term survival, as has been shown using a variety of techniques for LV functional assessment. Among a large series of 1690 consecutive patients who underwent dual-isotope–gated SPECT imaging, those patients in whom EFs were <45% were associated with reduced survival, irrespective of the perfusion defect size or severity.³¹ In addition, those patients with normal ESV of <70 mL or an EF of >45% had a very low cardiac mortality rate, despite severe perfusion abnormalities (Fig. 11-4). This group also examined the relative value of perfusion and function in the risk stratification in 2686 patients into low-, intermediate-, and high-risk categories for cardiac death and MI.³² LVEF was most predictive of death, and the amount of ischemia (summed difference score on perfusion imaging) was the best predictor of nonfatal MI. Functional information was found to be of incremental value in the prediction of cardiac death beyond the perfusion imaging parameters. The presence of ischemia did not influence prognosis in patients with LVEF <30%, due to the already high mortality rate.

LV function has long been a key determinant for survival following an acute MI. Recently, a study of 128 postinfarct survivors confirmed the value of gated SPECT imaging for risk stratification in post-MI patients, as an LVEF of <40% with this method was found to increase the risk of subsequent cardiac event by almost threefold.³³ The presence of a fixed or reversible defect had no independent predictive value in this study, although the latter finding may be a result of the censoring of high-risk patients who underwent early revascularization.

Differentiation of Etiology of Dilated Cardiomyopathy

The role of radionuclide image in heart failure is described in Chapter 22. An important step in the evaluation of new-onset heart failure is the distinction between LV systolic dysfunction due to CAD and other etiologies. In this regard, the addition of regional function data to perfusion data may be of benefit,³⁴ particularly the presence of regional dysfunction in coronary vascular territories, which is more consistent with ischemic cardiomyopathy etiology. Table 11-3 lists findings suggestive of ischemic and nonischemic etiologies for LV systolic dysfunction.

Assessment of Left Ventricular Dyssynchrony

Dyssynchrony refers to a temporal dispersion in the activation and contraction of the normally coordinated ventricle. Since, minor differences in the amplitude and timing of LV contraction exist in normally functioning hearts,³⁵ pathophysiologic dyssynchrony needs to be defined using threshold rarely encountered in the normal population. Thus, LV dyssynchrony is not an all-or-none phenomenon, but represents a continuum of severity. LV dyssynchrony is identified clinically by the presence of a bundle branch block on ECG (electrical dyssynchrony), which is an indicator of interventricular conduction delay and hence interventricular dyssynchrony.³⁶ The presence of a wide (>150 ms) left bundle branch block (LBBB) is currently considered the strongest predictor of improvement in LV function after cardiac resynchronization therapy (CRT) among patients with drug-refractory heart failure and severely reduced LVEF.³⁷ Dyssynchrony can also be intraventricular (within the LV), and characterized by global or regional intraventricular variations in myocardial contractility. Studies have shown intraventricular dyssynchrony to be more strongly associated with poor cardiac performance and adverse events, than interventricular dyssynchrony.³⁸ The mechanisms of LV dyssynchrony are poorly understood, but thought to be dependent on a complex interplay of numerous factors including severity of LV systolic dysfunction, electrical abnormalities (QRS width and pattern), and LV scar burden. In general, the prevalence of mechanical dyssynchrony increases with worsening systolic dysfunction and increasing QRS duration. Among patients with severely reduced LV systolic function, dyssynchrony has been reported in up to 75% of the patients.³⁹ Among all patients with systolic heart failure, the reported prevalence of mechanical dyssynchrony measured by echocardiography varies from 27% in patients with narrow QRS (<120 ms) to 89% in those with QRS duration >150 ms.^35,40 Traditionally, intraventricular mechanical dyssynchrony has been measured using echocardiographic techniques (m-mode and tissue Doppler imaging) that have poor inter- and intraobserver reproducibility.⁴¹ Contemporaneous echo approaches utilizing speckle tracking and real-time 3D echocardiography have better repeatability,⁴² but have not proven effective in predicting response to CRT.⁴² The reason for this dissociation between the presence of mechanical dyssynchrony and response to CRT is unclear, but is most likely related to the complexity of the CRT response, which is influenced by many other factors including location and extent of myocardial scar, location of the latest contracting myocardial segment and its relation with the LV lead of the biventricular pacemaker.

Radionuclide-based synchrony measurement utilizes phase analysis of regional or global time activity curves to determine timing of regional contraction, and can be performed using RVG or tomographic techniques (SPECT or PET). Since the vast majority of current cardiac radionuclide studies are gated SPECT, this approach has accrued the most supporting data, and will be focus of this review. The poor spatial resolution of SPECT makes it subject to partial-volume effects, resulting in a relatively linear relationship between myocardial thickening and myocardial count density in any segment of the myocardium.⁴³ This can be visually appreciated on gated SPECT images where the myocardium is brighter in systole. Thus the count activity curve of a myocardial sample (voxel) during a cardiac cycle essentially represents a myocardial thickening curve, albeit with poor temporal fidelity because of the 8- or 16-bin gating that is generally used for myocardial SPECT. Fourier transformation of the count-activity curve of the myocardium in phase analysis improves the temporal resolution of the gated SPECT images and also generates a continuous thickening curve that delineates the timing of contraction of a myocardial sample (Fig. 11-5).^44,45

In addition, the timing (phase) of the peak contraction of a myocardial sample is also identified (referred to as "onset of mechanical contraction") and can be compared to that of other myocardial samples. Data on thickening and the onset of mechanical contraction are collected for over 600 myocardial samples during a standard myocardial perfusion–gated SPECT acquisition, and allows for the comparison of the timing of thickening among the various samples. This information can be displayed as a phase histogram or a phase polar map (Fig. 11-6).

Interpretation of Dyssynchrony

Gated SPECT phase analysis parameters that have been validated to represent LV dyssynchrony are the histogram bandwidth (HBW): the range (in degrees) during which 95% of the myocardial samples initiate contraction, and the phase standard deviation (PSD): the standard deviation (in degrees) of the timing of contraction from all the myocardial samples, and entropy. Using Emory Cardiac Toolbox® (ECTb), gender-specific cut-offs have been reported, by which a PSD value of >24.4 degrees in men and >22.2 degrees in women or an HBW value of >62.2 degrees in men and >49.8 degrees in women identifies presence of dyssynchrony.⁴⁶ Phase analysis–derived PSD and HBW value of gated SPECT data has been known to have shown excellent reproducibility⁴⁷ in single-center studies, due to the automated generation of these parameters with minimal operator input. However, repeatability has not been testing in a multi-center setting. In general, PSD and HBW are considered to represent a measure of global LV dyssynchrony. The assessment of regional V dyssynchrony can be derived by partitioning of the global phase data in accordance with the standard 17-segment LV model.⁴⁸ The segmental mean phase value provides an assessment of regional differences in LV contraction, from which the segmental location of the site of latest activation (SOLA) can be determined.⁴⁸ It is important to note that assessment of dyssynchrony from gated SPECT is software dependent, in a fashion similar to the known variations in measurement of LV volume and EF.⁴⁹ It is known that, Quantitative-Gated SPECT® (QGS) excludes myocardial regions with the lowest 5% of phase amplitude in the derivation of the HBW, and therefore is expected to produce values of HBW that are systematically different from those obtained from ECTb.^46,50 Given these computational differences between software, it is important to use software specific cut-offs when evaluating dyssynchrony, and to utilize the same software to process-gated SPECT data when serial changes in LV dyssynchrony is to be determined. Despite the low temporal resolution, when compared to ERNA, the wider availability and the ability to simultaneously obtain comprehensive information on perfusion, function, and dyssynchrony (both global and regional) from a standard acquisition, makes gated SPECT a very attractive tool for dyssynchrony assessment.

Clinical Application of Dyssynchrony

The natural application of LV dyssynchrony assessment would be in guiding CRT in patients with medically refractory heart failure and severely reduced EF, where approximately two-thirds of patients selected based on clinical criteria (NYHA class II-IV, EF <35% and QRS >120 ms) will show improvement in symptomatic and or LV function. Thus, there is interest in using imaging approaches to improve patient selection and response rates. However, more recent iterations of selection criteria afford a class I indication only to patients with QRS >150 ms with LBBB pattern, where the response rates is >80%. Gated SPECT and ERNA studies have shown that presence of LV dyssynchrony and its severity prior to CRT determines LV reverse remodeling and symptomatic benefit following CRT.^51–55 While threshold values of abnormal dyssynchrony have been associated with CRT response in small, single-center studies, specific cut-off values of HBW or PSD, hitherto considered in isolation, have not been useful in improving patient selection for CRT. Recent studies have suggested an important role of myocardial scar burden in predicting CRT response,^56–58 and also a relationship between SOLA with the position of the LV lead of a biventricular pacemaker.^59–61 Gated SPECT is an established technique to imaging MI or scar, and its ability to identify SOLA by regional phase analysis to guide LV lead position has been recently reported.⁶² Identification of regional phase on gated SPECT in a population with HF, low EF has demonstrated the SOLA to be always located in the lateral wall among those with LBBB,⁶³ but only in 50% of patients with non–LBBB wide QRS. This finding may partly explain the high response rate to CRT in patients with LBBB, and suggests a role of image guidance in the placement of the LV lead in patients with non–LBBB QRS patterns. Indeed, single-center studies do suggest improved outcome when the LV lead is targeted to a viable myocardial segment with delayed activation.^64–66

The combined value of dyssynchrony, myocardial scar and LV lead concordance with SOLA, in predicting CRT response was evaluated in a prospective study of 44 HF patients undergoing CRT implantation.⁶⁴ The presence of baseline dyssynchrony and its change immediately following resynchronization was studied on gated SPECT with a novel "single-injection protocol." A prespecified algorithm comprising of (a) presence of baseline dyssynchrony, (b) scar burden of <40%, and (c) LV lead concordance with SOLA (Fig. 11-7), predicted acute improvement or no change in LV dyssynchrony with 93% specificity and 96% positive predictive value, with a 96% negative predictive value (NPV) for acute deterioration in dyssynchrony.

Figure 11-8 shows a representative example. Patients experiencing acute improvement or no change in LV dyssynchrony with CRT had lower composite outcome of death, heart failure hospitalization, and ventricular arrhythmia compared to those in whom dyssynchrony acutely deteriorated (Fig. 11-9), thus providing some mechanical insight into CRT response mechanisms.

Most patients with drug refractory, symptomatic HF, severe LV systolic dysfunction and a wide (>150 ms) LBBB QRS morphology will benefit from CRT if they do not have extensive scar. In these patients, the imaging of the severity and pattern of LV dyssynchrony is unlikely to offer additive value, but imaging to exclude extensive scar has direct relevance to CRT outcome. In patients with a narrow QRS complex, CRT has been shown to be detrimental even in the presence of echo evidence of LV dyssynchrony.⁴² In patients with non–LBBB types of conduction abnormalities, the potential role of imaging dyssynchrony remains to be determined.

The introduction of ECG gating and the resultant ability of SPECT to determine LV regional and global function has been an important addition to the scope of radionuclide MPI. LV function information provides critical information that has established diagnostic and prognostic value. In addition, it has expanded the application of MPI to other evolving areas such as LV dyssynchrony assessment.