This article appears in the following Europace issue: Spotlight Issue: Cardiac Imaging in EP and CRT [View the issue table of contents]
IMAGING IN CRT
Is nuclear imaging a viable alternative technique to assess dyssynchrony?
1 Department of Radiology, Emory University School of Medicine, 1364 Clifton Road, Atlanta, GA 30322, USA; 2 Department of Cardiology, Leiden University Medical Center, Albinusdreef 2, 2333 ZA Leiden, The Netherlands
* Corresponding author. Tel: +1 404 712 4024; fax: +1 404 712 7961. E-mail address: jchen22{at}emory.edu
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Abstract |
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Cardiac resynchronization therapy (CRT) has shown benefits in patients with end-stage heart failure (HF) (NYHA class III or IV), depressed left ventricular (LV) ejection fraction, and prolonged QRS duration (>120 ms). However, at least 30% of the patients who meet the above criteria show no response to CRT. It has shown with echocardiography that the presence of LV mechanical dyssynchrony is an important predictor for response to CRT. However, echocardiography requires expertise to produce reproducible and reliable results. The recent report from the Predictors of Response to Cardiac Resynchronization Therapy trial showed that under ‘real-world’ conditions the current available echocardiographic techniques including tissue Doppler imaging (TDI) and myocardial strain-rate imaging are not ready for routine clinical practice to assess LV dyssynchrony. It suggested that there is a need for better standardization and refinements of the echocardiographic screening tools currently used for the evaluation of LV dyssynchrony. This article reviews a technique such as phase analysis that allows measuring LV dyssynchrony from conventional electrocardiogram-gated single-photon emission computed tomography myocardial perfusion imaging with no additional procedure. Its advantages over TDI are its automation, repeatability, and reproducibility that are very promising in improving prediction of CRT response in HF patients.
Key Words: Heart failure, Cardiac resynchronization therapy, Left ventricular dyssynchrony, ECG-gated SPECT, Myocardial perfusion imaging
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Introduction |
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Heart failure (HF) affects >5 million people in the USA. Approximately 550 000 new cases are diagnosed annually and acute decompensated HF accounts for over 1 million hospital admissions per year.1
The estimated direct and indirect cost for HF in 2006 is $29.6 billion.2
Cardiac resynchronization therapy (CRT) has shown benefits in patients with severe HF.3 However, multiple CRT trials using the conventional selection criteria—end-stage HF (NYHA class III or IV), depressed left ventricular ejection fraction (LVEF) (<35%), and prolonged QRS complex on the surface electrocardiogram (ECG) (>120 ms)—have shown a significant percentage of patients (20–40%) failing to benefit from CRT.3–6 It has been recognized that electrical dyssynchrony as determined by QRS duration may not necessarily represent mechanical dyssynchrony and, therefore, may not represent the best predictor of CRT response.7–9 Assessment of LV mechanical dyssynchrony has been attempted with echocardiography, which shows promising results.10–14 However, the Predictors of Response to Cardiac Resynchronization Therapy (PROSPECT) study recently reported that under ‘real-world’ conditions the current available echocardiographic techniques including tissue Doppler imaging (TDI) and myocardial strain-rate imaging are not ready for routine clinical practice to assess LV dyssynchrony.15 The PROSPECT study suggests that there is a need for better standardization and refinements of the echocardiographic screening tools currently used for the evaluation of LV dyssynchrony. One of the major reasons of the unpleasant results of the PROSPECT trial is that echocardiographic measurement requires expertise to generate reliable and reproducible results that are necessary in order to more accurately and consistently predict CRT response.
Electrocardiogram-gated single-photon emission computed tomography (GSPECT) myocardial perfusion imaging (MPI) is the most widely used nuclear imaging procedure for diagnosis and management of coronary artery disease, which is the most common cause of chronic HF.16 It is widely available with superb standardization and reproducibility. Recently, a phase analysis technique has been developed to allow GSPECT MPI to assess LV mechanical dyssynchrony.17 It is a mathematical algorithm that can be applied to any conventional GSPECT MPI study and requires no additional acquisition. This technique is very promising in improving prediction of CRT response. In addition to its superb automation and reproducibility, the prognostic information obtained from three-dimensional (3D) perfusion images of the same patient can be very useful in the prediction of CRT response. For example, the presence and location of myocardial scar tissue, which has recently been shown to adversely affect response to CRT,18 may impact site selection for LV pacing lead placement. In this article, the phase analysis methodology is reviewed, and its clinical validations are summarized.
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Phase analysis of electrocardiogram-gated single-photon emission computed tomography myocardial perfusion imaging studies: technical essentials |
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Processing and quantification
Phase analysis has been implemented in the Emory Cardiac Toolbox (Emory University, Atlanta, GA, USA).19
Figure 1 illustrates its data flow. The input is a GSPECT MPI short-axis image. Every temporal frame of this image is searched in 3D to obtain regional maximal counts. These 3D samples can be displayed as gated polar maps as shown in Figure 1. Once the regional samples obtained from all temporal frames, the regional maximal count variation over the cardiac cycle is obtained. It has been shown that the variation of the regional maximal counts is nearly proportional to the myocardial wall thickening of the region.20,21 Then, the first-harmonic Fourier function is used to approximate the regional wall thickening curve to calculate a regional phase, which is related to the time interval when the region starts to contract [presumably, onset of mechanical contraction (OMC)]. Repeating the Fourier analysis for all regions over the left ventricle, an OMC phase distribution is obtained and submitted to quantitative assessment of its uniformity or heterogeneity, i.e. a measure of LV synchronicity. Five quantitative indices (listed in Table 1) have been used to assess LV dyssynchrony. Normal limits for these indices have been generated from GSPECT MPI studies of 45 male and 45 female normal subjects.17
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Reproducibility
Phase analysis is largely automatic. Intra-observer and inter-observer reproducibility of this technique has been evaluated in a recent study using 10 consecutive subjects with LV dysfunction (LVEF
35%) and 10 normal controls.22 For phase standard deviation and histogram bandwidth, the intra-observer correlation coefficients were 1.00 and 1.00, and the mean absolute differences between two reads by the same observer in different occasions were 0.8° and 1.4°, respectively. Inter-observer correlation coefficients were 0.99 and 0.99, and the mean absolute differences between two reads by two independent observers were 2.0° and 5.4°, respectively, for phase standard deviation and histogram bandwidth. The superior reproducibility of phase analysis to echocardiography is a promising advantage that may improve prediction of CRT response, since the 20–40% of the poor CRT outcome is based on echocardiographic results, and in none of these studies, GSPECT MPI was used.
Temporal resolution
Since GSPECT MPI studies are usually acquired as 8 or 16 frames/cardiac cycle, these data are perceived to have low temporal resolution. It is important to note that phase analysis uses continuous Fourier harmonic functions to approximate the discrete wall thickening samples. As shown in Figure 1, the phase difference between 8 vs. 16 frames/cycle is very small—0.5° (360° corresponding to one cardiac cycle), demonstrating that Fourier harmonic approximation improves the temporal resolution of the phase measurement. A recent simulation study based on a digital phantom has shown that in common clinical settings (
10 counts/myocardial pixel) phase analysis can detect phase delays using GSPECT MPI data acquired with 8 or 16 frames/cycle as well as though it is acquired using 64 frames/cycle but processed without Fourier analysis.23 This study indicated that the temporal resolution of phase analysis is equivalent to 1/64th cardiac cycle, when there are enough counts in the image.
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Phase analysis of electrocardiogram-gated single-photon emission computed tomography myocardial perfusion imaging: clinical validations |
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Validation with tissue Doppler imaging
Left ventricular dyssynchrony assessed by phase analysis has been compared with that assessed by 2D TDI in 75 patients with HF (NYHA function class III or IV), depressed LVEF (<35%), and wide QRS duration (>120 ms).24
These patients underwent 2D TDI and resting GSPECT MPI. The TDI data were evaluated by consensus by two experienced cardiologists who were blinded to the GSPECT MPI data. Peak systolic velocities and time-to-peak systolic velocities were obtained from the basal portions of the septal, inferior, anterior, and lateral wall, respectively. The delay in peak velocity between the earliest and latest activated segments was calculated as LV dyssynchrony. Phase standard deviation, histogram bandwidth, histogram skewness, and histogram kurtosis, measured by phase analysis of the GSPECT MPI data, were compared with LV dyssynchrony measured by 2D TDI. Good correlations were obtained for phase standard deviation vs. TDI LV dyssynchrony (r = 0.80, P < 0.0001) and histogram bandwidth vs. TDI LV dyssynchrony (r = 0.89, P < 0.0001).24
Left ventricular dyssynchrony assessed by phase analysis has also been compared with LV dyssynchrony measured by 3D TDI in 40 consecutive patients with end-stage HF (NYHA class III or IV), depressed LVEF (<35%), and prolonged QRS duration (>120 ms).25 These patients underwent 3D TDI and resting GSPECT MPI. The TDI data were processed by two experienced cardiologists who were blinded to the MPI data. Times to peak systolic velocity (Ts) are obtained from 12 segments based on a 12-segment model introduced by Yu et al.26 Then, the standard deviation of these times (Ts-SD) is calculated as an indicator of LV dyssynchrony. Correlation analyses showed good correlation for both phase standard deviation vs. Ts-SD (r = 0.74, P < 0.0001) and histogram bandwidth vs. Ts-SD (r = 0.77, P < 0.0001). When dividing the 40 patients into two groups according to Ts-SD (33 vs. <33 ms), both phase standard deviation (55.3° ± 13.6° vs. 25.1° ± 7.6°, P < 0.0001) and histogram bandwidth (186° ± 52° vs. 74° ± 24°, P < 0.0001) were significantly different between the two groups.25
These validation studies demonstrate that LV dyssynchrony assessed by phase analysis of GSPECT MPI is comparable to that assessed by TDI. They support the feasibility of evaluating LV dyssynchrony by GSPECT MPI and its applicability in a clinical setting.
Prediction of cardiac resynchronization therapy responses
Left ventricular dyssynchrony assessed by phase analysis has been evaluated to study whether it can predict response to CRT.27 Forty-two patients with severe HF (NYHA HF class III or IV), depressed LVEF (<35%), and prolonged QRS duration (>120 ms) were included. Thirty of the 42 patients were defined as responders according to improvement greater than one NYHA HF class after 6-month follow-up, and 12 were defined as non-responders (Figure 2). At baseline (pre-CRT), there were no significant differences in clinical characteristics between responders and non-responders except for the histogram bandwidth and phase standard deviation, which were significantly larger in responders when compared with non-responders. As determined by receiver operating characteristic (ROC) analysis, the optimal sensitivity and specificity of 70% was obtained for histogram bandwidth at a cut-off value of 135°, and those of 74% obtained for phase standard deviation at a cut-off value of 43°. The areas under the ROC curves were 0.78 and 0.81 for histogram bandwidth and phase standard deviation, respectively, indicating good predictive values. This study demonstrates that clinical response to CRT is related to the presence of LV dyssynchrony assessed by phase analysis of GSPECT MPI studies. The LV dyssynchrony quantification (histogram bandwidth and phase standard deviation) can be used to predict response to CRT.
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Conclusion |
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Phase analysis is a novel technique to measure LV dyssynchrony and predict response to CRT. It yields comparable results to TDI, and it appears that it may be superior to the current mostly echocardiographic techniques available because of its higher reproducibility, and more importantly, its potential for integrated assessment of myocardial ischaemia, infarction, viability, LV dysfunction, and LV dyssynchrony from the same GSPECT MPI study.
Conflict of interest: J.C. and E.V.G. receive royalties from the sale of Phase Analysis tool with the Emory Cardiac Toolbox. The terms of this arrangement have been reviewed and approved by Emory University in accordance with its conflict-of-interest practice. No conflict of interest is declared for the other authors (J.J.B., M.M.H., and M.J.B.).
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This work was supported in part by the 2006–2007 American Society of Nuclear Cardiology Foundation/GE Healthcare Research Award.
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