PET represents a state-of-the-art modality in cardiac imaging that allows the evaluation of quantitative physiological parameters (e.g., myocardial blood flow, glucose uptake, and oxidative metabolism) determined by the selected radiotracer. The intrinsic advantages of PET in comparison to SPECT technology such as higher count rates, more physiological tracers, and increased spatial resolution provide high-quality and quantitative images that boost the diagnostic and prognostic utility at a reasonable radiation burden.

Current PET scanners operate with list-mode acquisitions in order to obtain adequate datasets for the reconstruction of dynamic, static, and particularly (ECG-) gated images. The latter considers the ECG signal obtained in parallel to the acquisition and tracks wall thickening and changes in the detected cavity contours throughout the averaged cardiac cycle, typically binned into 8 or 16 frames (notably, phantom research has demonstrated that 8 or 16 frames per cycle Fourier phase analysis is equally effective to detect phase delays as with 64 frames per cycle non-Fourier analysis5). This processing provides quantitative estimations of left-ventricular cavity volumes and consequently, the derived left ventricular ejection fraction (LVEF).6,7 Thereon, a distinctive evaluation can be performed in order to estimate parameters of ventricular synchrony of contraction through phase analysis as illustrated in Figure 1.

Phase analysis was developed originally by Chen and colleagues,8 and has become an interesting value-added tool in nuclear imaging. In such analysis, a large number of transmural regions in the left ventricular myocardium (500-1000) are sampled by evaluating the myocardial counts detected throughout the re-binned frames of the averaged cardiac cycle. These three-dimensional count distributions are analyzed using a first-harmonic Fourier (sinusoidal) function (Figure 1) for every sample of the myocardium. This allows for the measurement of the phase offset and amplitude, which provides an index of myocardial wall thickening. The phase offset shows the difference between the start-time of the first frame and the time when the sinusoidal function crosses the DC component of the myocardial counts, which represents the average value of mechanical contraction for a particular pixel. This point of convergence is interpreted as the moment of onset of the ventricular contraction for the considered sample. Finally, the collection of all phase offsets corresponding with every spatial sample can be displayed in a color-coded histogram with an x-axis standardized to the length of the average cardiac cycle expressed in milliseconds, periodic degrees, or a relative percentage. Moreover, it is also possible to track the onset of mechanical relaxation from a multiharmonic analysis with count-drop correction, which would correspond with the diastolic mechanical synchrony.5 This last approach, however, has not been significantly evaluated in PET imaging.

The resulting phase histogram provides several descriptive parameters of the synchronicity and uniformity of contraction of the left ventricle (see Figure 2), both as a whole or following standard segmentation procedures. Described parameters include phase mean, phase standard deviation (SD), phase bandwidth (BW = 1.96 × SD), synchrony (S) , and entropy (E).9 The phase mean and SD represent the average moment of phase offsets in the whole LV and the corresponding standard deviation over all myocardial samples. Phase bandwidth represents the interval where 95% of the values occur in the histogram (i.e., the range during which 95% of the ventricle initiates mechanical contraction). Entropy and Synchrony, as proposed by O’Connell et al10 for planar imaging, then generalized to SPECT,11,12 are slightly different metrics combining the amplitude and phase of dyssynchrony during ventricular contraction, not influenced by the histogram borders or by phase similarity.13

Since the average cycle is obtained over several hundreds of gated cardiac cycles (multiple R-R intervals), it is possible that phase analysis may be affected when substantial rhythm or motion disturbances are encountered (e.g., in patients with atrial fibrillation or frequent ventricular extrasystoles).14^-16 Correction techniques of gating errors are therefore warranted in order to obtain robust measurements in clinical practice.17

In contrast with SPECT, there is a relative paucity of publications on the feasibility, validation, average parameter values in populations of interest, and clinical utility regarding PET (dys)synchrony imaging, as evidenced in Table 1. Focus has been placed in the utility of PET synchrony assessment for the distinction of patients who may benefit from cardiac resynchronization therapy (CRT) considering that the rate of nonresponders has stabilized at around 30% of patients, as selected by ECG, LVEF, and clinical heart failure (HF) criteria following current guidelines.15,18 In the setting of CAD, the link between myocardial ischemia and mechanical synchrony has been studied primarily under the working assumption that myocardial blood flow (the quantitative perfusion feature offered by PET but not SPECT imaging) may represent a determinant in the status of ventricular mechanical synchrony and its response during pharmacological stress (vide infra).

A large number of published reports on mechanical ventricular synchrony evaluated with PET have utilized ¹⁸F-FDG and ⁸²Rb as viability and perfusion radiotracers, respectively. In fact, only one study has evaluated correlates and determinants of synchrony measurements from ¹³N-ammonia PET perfusion data,19 while no study has utilized ¹⁵O-water for such evaluation.

Table 2 outlines the reports that have suggested reference values (i.e., normal values and cutoff points for distinguishing from pathological populations) in the evaluation of mechanical synchrony with PET and SPECT (selected for comparison). In fact, when analyzing available reports, it is noticeable how assumptions of robustness, and in some cases of normal values, have been directly translated from SPECT studies. Although it is true that PET could be understood as a refined version of SPECT imaging due to lower noise, higher tracer counts, lower radiation burden, and improved spatial resolution,15 it is of great relevance to characterize how these factors may influence the estimation of normal and pathological synchrony values in order to promote the utilization of PET synchrony evaluation with different protocols and software packages. In this sense, the study by Cooke et al complementarily compared their estimates to those suggested in previous SPECT studies concluding that very likely BW and SD are robust and reproducible measures of synchrony across stressors, physiologic states, acquisitions, reconstruction methodologies, and processing algorithms.30 Further in general, factors like age, LVEF, and heart rate may affect the dyssynchrony results. SPECT studies have reported variability in volumes and ejection fraction by different software.31,32 Also, larger values of phase bandwidth, phase SD, and entropy have been reported for men compared to women in SPECT studies.33,34 These assumptions, however, should be utilized with caution when evaluating PET-derived synchrony.

Another factor of interest is the availability of several commercial software packages that offer phase analysis. Overall, phase analysis has been implemented in the Emory Cardiac Toolbox 4DM and QGS software. Variability across packages has recently been addressed by Okuda et al,35 but only in the case of SPECT acquisitions. Cross-validation efforts in synchrony evaluation with PET are therefore warranted to enable comparison of measured values between imaging centers using different software programs.

In summary, ventricular mechanical synchrony as measured by PET imaging may be of value in the evaluation of patients with suspected myocardial ischemia leading to myocardial stunning and in patients with HF with an indication for CRT due to the suspected substrate of mechanical dyssynchrony. At the same time, it is likely that PET synchrony evaluation may hold prognostic values in patients with HF and in patients with CAD, in particular with multivessel disease BW of which and the SD of the phase after exercise are significantly increased. In addition, phase analysis is able to detect the LV mechanical dyssynchrony due to the vasomotion changes associated with occult atherosclerosis in patients with normal coronary angiography findings. Whether PET-measured synchrony can offer diagnostic value beyond or at an earlier stage than mainstream functional parameters, may serve as a tool for refining selection of CRT recipients, and should be incorporated in the clinical exercise of risk stratification, remains to be elucidated. The application of PET synchrony evaluation together with the evaluation of myocardial scar (fibrosis) has the potential to improve selection for access to CRT in those patients most likely to improve the clinical effectiveness and cost effectiveness of CRT for heart failure.

Notably, the intrinsic advantages of PET, including its wide range of physiological radiotracers available and its full quantitative capabilities, set the ground for the value addition to the phase analysis of ventricular synchrony in establishing the so-called “one-stop shop”15 in which perfusion or viability, scar location, and extent, ventricular volumes, and function (both systolic and diastolic), and synchrony36 can be simultaneously evaluated. Moreover, comprehensive imaging can be boosted through the utilization of currently available hybrid equipment (PET/CT and PET/MR) that allows for complementary anatomic information (e.g., epicardial fat, calcium score, and venous system structure) to be obtained within the same imaging session. Cardiac MR (CMR) is, in addition to PET, is expected to provide—partly confirming, partly complementary—tissue-specific anatomic (fiber, fat, muscle, and blood) and pathophysiological (edema, infarction, microvascular obstruction, and tumor) information, and could add tissue strain data which can be used as a measure of cardiac synchrony to complete a disease-specific cardiac model, as was recently reported for a carotid plaque inflammation model using MR-PET/CT,37 and in a cardiac sarcoidosis model using CMR, PET, and ultrasound,38 and in a hypertrophic cardiomyopathy (HCM)-phenotype model using CMR, PET, and ultrasound.39 The recently published joint position statement of the ESCR and EANM also states application of CMR-PET is feasible, robust, and promising.40 We therefore expect cardiac gated CMR-PET to provide a new model to help understand cardiac synchrony in future studies.

Evaluation of PET ventricular mechanical synchrony has arguably emerged as an extrapolation of prior phase analysis using SPECT imaging. As such, there are variations in reference values, and extensive evidence on its utility for the evaluation of ventricular dysfunction with diagnostic and prognostic purposes as well as for better selection of CRT recipients is slowly emerging.