Novel algorithm for quantitative assessment of left ventricular dyssynchrony with ECG-gated myocardial perfusion SPECT: useful technique for management of cardiac resynchronization therapy
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- Kiso, K., Imoto, A., Nishimura, Y. et al. Ann Nucl Med (2011) 25: 768. doi:10.1007/s12149-011-0525-8
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Cardiac resynchronization therapy (CRT) is the established treatment for patients with chronic and severe heart failure, and it has been reported that the presence of left ventricular (LV) dyssynchrony is one of the most important factors which predict positive response of this therapy. In the present study, we developed new software algorithm for quantitative assessment of LV dyssynchrony from ECG-gated myocardial perfusion SPECT (GMPS), and evaluated its utility for the management of CRT.
Thirty-three patients with chronic severe heart failure were studied. GMPS was performed with 16 frame per-cardiac-cycle before and 6 months after CRT and LV end-diastolic volume, end-systolic volume (LVESV), ejection fraction (LVEF) were calculated by QGS software. We generated the time–activity curve per-cardiac-cycle in 4 myocardial segments by Fourier transform curve-fitting of the 16 serial count values, and measured the time from R-wave to the maximum-count point [time to end-systole (TES)] in each. For the evaluation of the degree of LV dyssynchrony, we used the maximum difference in TES (ΔTES) among the 4 segments which corrected for R–R time as dyssynchrony index (DI). Moreover, DI at baseline evaluated by GMPS was compared with the echocardiographic index of LV dyssynchrony; maximum difference of time to peak velocity (ΔTPV) evaluated by tissue Doppler imaging (TDI).
DI before CRT showed a significant correlation with the LV function, such as LVEF, LVESV (DI vs. LVEF; r = 0.57, P < 0.0001. DI vs. LVESV; r = 0.64, P < 0.0001). The study subjects were divided into 2 groups, responder group (R-Gp) with LVEF increase >10% or LVESV decrease >10% and non-responder group (NR-Gp). DI before CRT was significantly larger in R-Gp than in NR-Gp (25.9 ± 22.2 vs. 10.8 ± 8.9, P = 0.01). In R-Gp, DI showed a significant decrease after CRT (25.9 ± 22.2 → 13.6 ± 10.9, P < 0.05). DI at baseline measured by GMPS correlated significantly with ΔTPV at baseline measured by TDI (r = 0.38, P < 0.05).
This new algorithm for the estimation of LV dyssynchrony might be comparable to TDI, and contributes to the prediction and the evaluation for the response of CRT.
KeywordsCardiac resynchronization therapy (CRT)Left ventricular dyssynchronyECG-gated myocardial perfusion SPECT
Cardiac resynchronization therapy (CRT) has been utilized for patients with advanced heart failure, and numerical studies have reported that it improved the patients’ prognosis and quality of life [1–4]. Although CRT is commonly applied for the selected patients according to the ACC/AHA heart failure guidelines [5, 6], 20–30% of the patients show poor functional improvement [1, 7]. Therefore, the prediction of therapeutic improvement of LV function is essential for the decision of CRT indication. Prolonged QRS duration in ECG, which is one of the major criteria of CRT indication, may be the parameter related to LV dyssynchrony, but it is an indirect estimation. Recently, echocardiographic methods, such as M-mode, pulse Doppler imaging, and tissue Doppler imaging (TDI), are utilized for the direct and quantitative assessment of LV dyssynchrony. TDI especially provides precise assessment of the difference in timing of regional myocardial contraction by measuring regional time to peak velocity, and it is now used as one of the standard methods for quantitative analysis of LV dyssynchrony [8, 9].
In radionuclide imaging techniques, ECG-gated myocardial perfusion SPECT (GMPS), which enables to examine LV myocardial perfusion and function simultaneously, will also contribute to the quantitative assessment of LV dyssynchrony. Because GMPS data contain the information about regional wall thickening in a cardiac cycle, which is estimated by the change of regional wall counts based on the partial volume effect [10–13] of SPECT system. Actually, some studies with phase analysis technique, which enables the assessment of LV dyssynchrony by change of regional wall counts, have already revealed the importance of LV dyssynchrony for the prediction of response of CRT [14–16]. However, the software of phase analysis is packaged to the latest workstations only; the cost of this analysis is so expensive that the availability of this technique is extremely limited, compared with echocardiographic analysis.
In this study, we developed a new software program, which is applicable to the ordinary personal computers, to quantify the degree of LV dyssynchrony using GMPS data, and evaluated its utility for the management of CRT. We additionally compared the assessment of LV dyssynchrony by GMPS with that by TDI. This study is confirmed to the 2005 version of the Ethical Guideline for Clinical Study (Ministry of Health, Labor and Welfare of Japan).
Clinical characteristics of study population (n = 33)
58 ± 16
NYHA functional class
2.7 ± 0.5
QRS duration (ms)
160 ± 30
25.3 ± 12.0
229.1 ± 151.1
289.9 ± 155.4
ECG-gated myocardial perfusion SPECT
GMPS with technetium-99m (99mTc) sestamibi was performed at rest before (2.2 ± 1.8 months) and 6 months (6.6 ± 1.3 months) after CRT. For all patients, SPECT image acquisition was performed in a supine position 1 h after intravenous injection of 600 MBq of 99mTc-sestamibi. To remove tracer retention in liver and gallbladder, the patients took light meal or milk before image acquisition. Thirty projection images were obtained over 180° in 6° increments with 50 beats per view, using a dual-headed SPECT system (VERTEX; ADAC laboratories, Milpitas, CA) equipped with a low-energy general-purpose collimator. An ECG R-wave detector provided a gate to acquire sixteen frames per cardiac cycle. The image resolution in the transaxial plane was 16 mm full-width at half-maximum. Data was stored in 64 × 64 matrix. The energy discrimination was centered on 141 keV with a 20% window. To generate transaxial tomograms from the gated projection data and reconstruct oblique angle tomograms, a ramp filter and a Butterworth filter (order 8, cutoff 0.27 cycle/pixel) were used. Acquired image data were transferred to PEGASYS workstation (ADAC Laboratories), and we measured LV volumes [LV end-systolic volume (LVESV), LV end-diastolic volume (LVESV)] and LV ejection fraction (LVEF) using QGS software developed by Germano [17, 18], and also measured the size of perfusion defects: %defect size (%DS), which were calculated from the area of perfusion abnormality lower than −2SD compared with normal files, using QPS software.
Assessment of LV dyssynchrony based on GMPS Data (Fig. 1)
Tissue Doppler imaging
Two-dimensional (2D) TDI was performed in the left decubitus position with the echocardiography system (Vingmed Vivid Seven, GE-Vingmed) at almost the same timing and those images were stored for off-line analysis (Echopac, GE-Vingmed). For the analysis of myocardial tissue velocity curves, the sample volume was placed in the LV basal GMPS before the implantation of CRT. The images were acquired from the apical four-, three-, two-chamber views, portions of anterior, inferior, septal, and lateral wall, using apical long axis view, the 2- and 4-chamber view images (total 12 sample points). The maximum difference between time to peak systolic velocities (ΔTPV) among the four portions was used as an index of LV dyssynchrony.
Statistical analysis was performed with StatView statistical package (SAS Institute, Cary, NC). All data ware expressed as the mean ± standard deviation. Patients’ data were compared using the paired or unpaired Student’s t test when appropriate. For the evaluation of correlations, Pearson’s correlation analysis was performed. For all tests, a probability value of 0.05 or less was considered significant.
The study patients were classified into two groups based on LV functional response to CRT, 18 responders and 15 non-responders. The responders were defined as those with improvement of LVEF >10% and/or percent reduction of LVESV >10% during the 6-month follow-up. In responders, LVEF changed from 22.2 ± 12.2 to 30.0 ± 13.3% and LVESV from 278.8 ± 164.6 to 179.5 ± 135.0 ml. In non-responders, LVEF changed from 30.1 ± 10.7 to 28.2 ± 11.2% and LVESV from 169.0 ± 123.1 to 178.1 ± 118.1 ml.
Baseline characteristics of responders (n = 18) and non-responders (n = 15)
55 ± 18
61 ± 14
2.8 ± 0.5
2.5 ± 0.5
16.3 ± 14.5
21.1 ± 15.3
22.2 ± 12.2
30.1 ± 10.7
278.8 ± 164.6
169.0 ± 123.1
342.0 ± 164.3
228.9 ± 135.0
25.9 ± 22.2
10.8 ± 8.9
Multiple logistic regression analysis
Comparison to TDI parameter
We developed a new software program to quantify the degree of LV dyssynchrony from the GMPS data, and evaluated its utility for the prediction and evaluation of therapeutic effects of CRT in this study. The results revealed that LV dyssynchrony index analyzed with this new software program contributes to the prediction of patients with functional improvement by CRT, and to the evaluation of improvement of LV dyssynchrony by CRT. Interestingly, patients with worse LV functions showed higher DI in baseline. Moreover, the degree of the DI improvement by CRT tended to correlate with that of the LV functional improvement. The result that DI correlated with the conventionally used echocardiographic index, ΔTPV derived from TDI, supported the capability of DI. Furthermore, we found that DI is the best predictor of CRT responders by multiple logistic regression analysis in comparison with other factors such as age, gender, NYHA functional class, %DS, and LV functions (Fig. 8).
CRT has been proved to be effective for improving LV function for patients with chronic severe heart failure in several large-scale clinical trials [1–4], but it has been noted that up to 30% of the patients receiving CRT show poor response [1, 7]. Since CRT is an invasive and expensive therapy, the prediction of therapeutic outcome should be cautiously performed before therapy. Regarding the selection of candidates for CRT, Bax et al.  reported that LV dyssynchrony investigated by TDI is the most useful parameter which predicts the effectiveness of CRT, other than the conventional indication criteria such as prolonged QRS duration, etc. However, the echocardiographic analysis has limitations in terms of reproducibility and inter-observer variability in measurement. Chung et al.  revealed in PROSPECT trial that no single echocardiographic measure of LV dyssynchrony improve the patient selection for CRT beyond the conventional guidelines and speculated that it would be due to poor reproducibility and inter-observer variability in the echocardiographic measurement.
On the other hand, our newly developed software program using GMPS data is based on the automatically performed QGS software developed by Germano et al. [17, 18], and therefore it may provide better reproducibility and less inter-observer variability than the echocardiographic measurement. For that matter, it will promise as a mean for the objective investigation of LV dyssynchrony. Moreover, it is highly contributable in making the assessment of LV dyssynchrony in combination with that of myocardial viability. Since it has been previously reported that ischemic heart failure patients with large nonviable segments show poor response for CRT , myocardial viability is also recognized as the important factor which influence the response of CRT. For that matter, the GMPS method, which provides simultaneous assessment of LV dyssynchrony and myocardial viability, has a value as one-stop shop for the management of CRT. However, in contrast to the previous reports, %DS calculated from the area of perfusion abnormality lower than −2SD compared with normal files did not show a significant difference between responders and non-responders in this study. We suppose that it may be attributed to a small number of patients with large defect size in our study.
In radionuclide techniques, phase analysis with GMPS was firstly developed by Emory university group [21, 22]. Henneman et al.  reported the importance of LV dyssynchrony evaluated by phase analysis, which was comparable to TDI, for the prediction of CRT response. Moreover, they also investigated the predictive cut-off value with ROC analysis . As I have described, phase analysis is one of the useful tools for the estimation of LV dyssynchrony, however, this software has been bundled with latest workstations only. So, thinking of the cost and availability, there is a big disadvantage in this phase analysis. On the contrary, our new software program is installable and available to the ordinary personal computers. Therefore, this software is superior to phase analysis technique in terms of cost and availability.
Yamamoto et al. has also developed “CardioGRAF” software for the assessment of LV dyssynchrony. The algorithm of this software, which is different from that of our method and phase analysis, is based on the changes of volumes of regional LV cavity during a cardiac cycle [23, 24]. Furthermore, the clinical usefulness of this software for the evaluation of CRT response has been also reported [25, 26]. However, this software is applicable to the GMPS data obtained by p-FAST (Perfusion-Function Assessment for myocardial SPECT) analysis only. On the contrary, our new algorithm can be utilized for every software, not only QGS software, which can measure the maximum counts and segmental %peak activity. Thinking of availability, our new method might have advantage over this cardioGRAF.
Several limitations of this study must be considered. Firstly, this study involved small number subjects. Therefore, the results must be validated with larger study population. Secondly, this study was analyzed with the 4-segment myocardial model. Phase analysis and TDI can estimate LV dyssynchrony in more detail with larger myocardial segments. So, we have to improve our software program to deal with more segments, such as 17- or 20- segment model. And it is necessary to investigate the suitable number of myocardial segment model for the prediction and estimation of CRT response.
Our newly developed software program for quantitative estimation of LV dyssynchrony, which is based on the differences of timing in LV regional wall thickening derived from GMPS, can provide important information about the decision-making and evaluation of CRT. And this new algorithm might be comparable to TDI which has been utilized as the only modality for the estimation of LV dyssynchrony.