Journal of Nuclear Cardiology

, Volume 25, Issue 6, pp 2039–2043 | Cite as

Mechanical dyssynchrony with phase analysis of gated SPECT: Nap time is over

  • Wael AlJaroudiEmail author

Cardiac resynchronization therapy (CRT) improves left ventricular (LV) remodeling, quality of life, and survival among patients with heart failure and reduced ejection fraction (EF < 35%) and electrical dyssynchrony (wide QRS duration).13 However, a significant proportion of patients do not derive the expected benefit from such expensive and invasive procedure.4 In 2011, Goldengerb et al. identified 7 factors from the Multicenter Automatic Defibrillator Implantation Trial With Cardiac Resynchronization Therapy (MADIT-CRT) trial that improved patient selection and predicted better CRT response;5 these included female gender, non-ischemic cardiomyopathy, left bundle branch block (LBBB), QRS ≥ 150 ms, prior hospitalization for heart failure, left ventricular end-diastolic volume index ≥ 125 ml/m2, and left atrial volume index less than 40 ml/m2. Shortly after, the 2012 guidelines for CRT implantation were updated and recommended CRT for patients with EF ≤ 35%, NYHA class ≥ II with LBBB, and QRS ≥ 150 ms (the only class I indication) as compared to a QRS threshold ≥ 120–130 ms with 2008 guidelines.6

The more stringent QRS threshold for CRT implementation was meant to choose patients with greater electrical dyssynchrony, thus greater mechanical dyssynchrony, and therefore those with higher chance of CRT restoring synchronicity of myocardial contraction. However, electrical and mechanical dyssynchrony are not interchangeable,7,8 which explains in part the remaining high rate of non-responders.9 Because of its non-invasiveness, low cost, and wide availability, significant effort and research were placed on identifying mechanical dyssynchrony parameters with echocardiography that would be best predictive of CRT response. Indeed, an exponential increase in the number of research papers was observed in the field of echocardiography between 2004 and 2008 exploring dozen of parameters with 2D, 3D echocardiography, strain, strain rate, and many others (Fig. 1). Promising single-center data were published, while others had conflicting data, until the negative and conclusive results of PROSPECT trial, a multicenter study that tested many echocardiography parameters (interobserver and intraobserver variability 4%–24% and 7%–72%, respectively) all of which failed to predict CRT response.10 Shortly thereafter, interest in mechanical dyssynchrony with echocardiography took a significant hit, and despite recent efforts to revive it,11 the number of publications kept on declining dramatically (Fig. 1).
Figure 1

Trend on the number of publications on mechanical dyssynchrony and response to CRT. The graph illustrates the decline in echocardiography publications after the negative results of the PROSPECT trial. On the other hand, the publications with the other imaging modalities, although smaller in absolute number, have steadily been rising. CCT, cardiac computed tomography; CMR, cardiac magnetic resonance; SD, phase standard deviation; SPECT, single-photon emission computed tomography

In 2005, Chen et al. published one of the first papers on mechanical dyssynchrony using phase analysis concept from gated single-photon emission computed tomography (SPECT).12 Briefly, a 3D count distribution is extracted from each of the LV short-axis datasets; a 1D fast Fourier transform is applied to the count variation over time for each voxel, generating a 3D phase distribution that describes the timing of LV onset of mechanical contraction over the entire R–R cycle.12 Unlike echocardiography, SPECT myocardial perfusion imaging (MPI) provides a single parameter to define mechanical dyssynchrony (phase analysis derived standard deviation SD) which is reproducible, repeatable on serial imaging testing, and easy to derive.8 Shortly after, Henneman et al. showing that a phase SD > 43° was an independent predictor of CRT response.13 In the following years, significant data were published on phase analysis and mechanical dyssynchrony. It was shown to predict ICD shock,14 and all-cause mortality.15,16 In addition, it was tested and validated with PET imaging.17 However, phase analysis faced several challenges including; (1) different vendors have different software and values without any way to standardize; (2) limited temporal resolution despite complex mathematical way to bypass it; (3) noise and artifact from areas with significantly reduced perfusion due to scar; (4) SPECT myocardial perfusion imaging is not performed routinely prior to CRT unlike echocardiography; and (5) limited data post-CRT placement as it requires repeat testing and tracer injection.

Moreover, data have shown that scar burden and location as it relates to LV lead placement are two important parameters that must be taken into account when deciding on CRT.8,18 Fortunately, both parameters are well defined with SPECT MPI. In a pioneer and well done prospective single-center study, Friehling et al. showed that an algorithm incorporating the presence of baseline mechanical dyssynchrony with phase analysis, limited myocardial scar burden, and LV lead concordance with area of latest onset mechanical contraction predicted response to CRT.19 Unfortunately, a multicenter large prospective randomized clinical trial to validate these findings could not be funded despite serious efforts to launch it.

During the same period, there has been several papers evaluating the role of cardiac computed tomography (CCT) and magnetic resonance (CMR) in guiding patient selection and predicting CRT response, whether by identifying scar burden, mechanical dyssynchrony, and coronary vein anatomy for best LV lead placement8 (Fig. 1). In patients with LBBB, two types of LV electric activation patterns have been described by non-contact mapping: U-shaped pattern which is caused by a line of block in the propagation direction of electrical activation; and non-U-shaped pattern.20 However, because of its invasiveness, its routine application has been limited. Using recent advances in CMR techniques, this electrical activation map can now be performed non-invasively, yielding similar data to the non-contact mapping. Indeed the U-shape contraction pattern with CMR was shown to have higher response rate with CRT.21 However, the technique remains limited to specialized centers and time consuming. Still, it is interesting to note the increase research in non-echocardiographic imaging (nuclear, CCT, and CMR) as opposed to echocardiography over the last decade in relation to mechanical dyssynchrony and optimizing patient selection for CRT response (Fig. 1).

In the current paper, and in an effort to translate the recently described electrical activation map by CMR into the nuclear realm, Tao et al. retrospectively evaluated 58 patients with NYHA class ≥ 2, EF < 35%, and LBBB who had resting SPECT MPI and subsequently underwent CRT or CRT-D.22 Using phase analysis, the baseline phase SD was determined from the histogram plot. Also, the mean phase angle of each segment was displayed on a 13-segmentation polar map generating different contraction patterns.22 Patients were divided almost equally as having U-shape versus non-U-shape contraction pattern. Both groups were on optimal medical therapy, had similar comorbidities and LV remodeling with the only exception of higher phase SD among those with U-shape contraction pattern. After 6 months of follow-up, 90% of those with U-shape contraction pattern responded to CRT versus 50% of those with non-U-shape contraction pattern. The only 3 that did not respond in the U-shape contraction pattern group included patients with either phase SD < 43°, significant scar burden, or non-concordant LV lead. After adjustment for QRS, scar and phase SD, U-shape contraction pattern remained an independent predictor of CRT response (odds ratio 16.0, p = 0.012).

It is important to note that CRT response was defined as increase in LVEF ≥ 5%. Although change in LV end-systolic volume index or improvement in NYHA class were not part of the definition of CRT response, CRT responders did have significant decrease in LV end-diastolic and systolic diameters. Furthermore, those with U-shape contraction pattern had significant improvement in NYHA class (43% class I post-CRT vs. 0% pre-CRT). Also, while QRS < 150 ms was not an exclusion criterion, only 5 had QRS < 150 ms, four of which did not respond. The relatively high response rate among those with non-U-shape contraction pattern is bit surprising; however, given the fact that the majority had non-ischemic cardiomyopathy (90%), and QRS ≥ 150 ms, it makes sense.

The current study is a like a breath of fresh air awakening the interest in phase analysis and mechanical dyssynchrony as a whole after a long nap in the hope of identifying CRT responders. It is not surprising that U-shape contraction pattern outperformed phase SD cut-off value. A high phase SD means significant variation in the onset of mechanical contraction, but does not specify the shape of contraction; indeed, patients with phase SD ≥ 43° can have either contraction pattern. The idea of visual evaluation of a polar map to make a clinical decision is not new; in echocardiography for example, apical sparing pattern seen on global longitudinal strain polar map in patients with increased LV thickness identifies cardiac amyloidosis in most patients, and outperforms and single strain cut-off value.23 More importantly, the identification of U-shape contraction pattern was relatively easy to assess visually and reproducible in 91% of cases. It is simple to incorporate the findings of the study in an algorithm to guide patient selection for CRT (Fig. 2).
Figure 2

Proposed algorithm for optimizing patient selection for CRT. CRT, cardiac resynchronization therapy; CT, computed tomography; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; MPI, myocardial perfusion imaging; MR, magnetic resonance; NYHA, New York Heart Association; SPECT, single-photon emission computed tomography

Almost all of the patients in the current study are considered to have class I indication for CRT based on the updated guidelines.6 Still, 28% (16/58) of “ideal guidelines candidates” did not respond. While the U-shape contraction pattern identified a subgroup that responded almost entirely 90%, still around 50% of those with non-U-shape contract pattern (almost 29% of the entire cohort, 17/58) responded. Playing devil’s advocate, one finds himself in a dilemma: using only the updated guidelines would result in wasting 28/100 CRT; on the other hand, risk stratifying further with U-shape contraction pattern, would result in denying 29 patients out of 100 CRT to which they would have responded.

Where do we go from here? The next step would be to validate the results. As a start, it would be helpful to retrieve from the prior published papers on phase analysis and CRT response, the actual contraction polar maps and blindly identify whether it is U-shape or not; then, one would re-analyze the data and assess whether the U-shape pattern indeed outperforms phase SD. The next step is to conduct a prospective multicenter randomized trial (Table 1). The time is now.
Table 1

Design for randomized clinical trial on optimizing patient selection for CRT with mechanical dyssynchrony by phase analysis

Patient selection

 Inclusion criteria

LVEF ≤ 35%


LBBB & QRS ≥ 150 ms




Day 0



 6 minutes walk test



Phase SD ≥ 43° & U-shape contraction pattern

Phase SD < 43° or non-U-shape contraction pattern


1:1 CRT on/CRT off

1:1 CRT on/CRT off

6 months



 6 min walk test




Cross over

CRT off/CRT on

CRT off/CRT on

12 months



 6 minutes walk test




Patients with LVEF ≤ 35%, LBBB, QRS ≥ 150 ms and NYHA class II-III on optimal medical therapy (i.e., meeting Class I indication according to the 2012 CRT guidelines) will be enrolled. Patients will undergo echocardiogram, 6 minutes walk test and resting SPECT MPI. Using phase analysis, contraction maps will be generated and categorized into U-shape and non-U-shape. Subsequently, patients will be grouped into those with phase SD ≥ 43◦ AND U-shape contraction pattern versus those with either phase SD < 43◦ OR non-U-shape contraction pattern. All patients will undergo CRT with LV lead placement at the area of latest onset mechanical contraction and minimal scar burden. However, each group will undergo 1:1 randomization to CRT on/CRT off. After 6 months, patients will undergo repeat echocardiogram, 6 minutes walk test and rest SPECT. CRT response will be defined as decrease in LV ESVi ≥ 20% with EF improvement ≥ 5%. Secondary endpoints will include improvement in NYHA class, 6 minutes walk test and normalization of phase SD. Finally, patients will undergo cross over (those with CRT on will go to CRT off and vice versa) with repeat follow-up testing in 6 months

CRT, cardiac resynchronization therapy; ESVi, end-systolic volume index; LBBB, left bundle branch block; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; SPECT, single-photon emission computed tomography





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Copyright information

© American Society of Nuclear Cardiology 2017

Authors and Affiliations

  1. 1.Division of Cardiovascular MedicineClemenceau Medical CenterBeirutLebanon

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