Introduction
Cardiac resynchronization therapy (CRT) has become an established therapy for patients with end-stage heart failure [
1]. However, up to 30% of the patients do not respond to CRT when selection is based on the traditional clinical and electrocardiographic criteria [New York Heart Association (NYHA) functional class III or IV, left ventricular ejection fraction (LVEF) <35%, and QRS duration >120 ms] [
2]. In the search for better selection criteria for CRT, it has been shown that patients with LV dyssynchrony have a higher likelihood of a positive response to CRT [
3‐
8]. Over the past few years, the assessment of LV dyssynchrony has been studied extensively with echocardiography.
The most frequently used technique is tissue Doppler imaging (TDI), which permits evaluation of timing of regional myocardial velocity and comparison of different regions yields information on LV dyssynchrony.
Bax et al. [
3] have used a four-segment model to assess LV dyssynchrony (four basal LV segments: anterior, lateral, inferior and septal) and reported that a delay ≥ 65 ms among the four segments was a strong predictor of response to CRT. Other authors extended the analysis by evaluating the activation pattern of the entire LV. This method, originally described by Yu and co-workers [
6‐
8], uses the standard deviation (SD) of electromechanical activation times based on a 12-segment model of LV (Ts-SD). The authors investigated 56 patients with heart failure who underwent CRT implantation and demonstrated that a cut-off value of 34.4 ms for Ts-SD could predict reverse LV remodeling after CRT with a sensitivity of 87% and a specificity of 81% [
7]. However, to calculate this parameter of LV dyssynchrony, three apical views need to be acquired separately. A 3-dimensional (3D) TDI imaging modality (tri-plane TDI) has become available to overcome this limitation. Tri-plane TDI allows simultaneous acquisition of all LV segments during the same heartbeat rendering the technique more precise than the 2-dimensional (2D) TDI equivalent. Another recent development is the use of gated myocardial perfusion single photon emission computed tomography (GMPS) for assessment of LV dyssynchrony [
9,
10]. A count-based method has been developed to extract phase information from the regional LV count changes throughout the cardiac cycle, and this phase information is related to the time interval when a region, in the 3D LV wall starts to contract (phase analysis). This technique has recently been implemented in the Emory Cardiac Toolbox as a diagnostic tool for assessment of LV mechanical dyssynchrony [
9].
To further validate the use of GMPS with phase analysis for the assessment of LV dyssynchrony, a direct comparison with tri-plane TDI was performed in a cohort of heart failure patients.
Discussion
The main findings of the present study can be summarized as follows:
(1) LV dyssynchrony assessment with phase analysis on GMPS is feasible in heart failure patients screened for eligibility for CRT implantation. The phase analysis variables histogram bandwidth and phase SD show good correlation with LV dyssynchrony as measured with tri-plane TDI (Ts-SD), suggesting that GMPS phase analysis can be used to quantify LV dyssynchrony. (2) Patients with substantial LV dyssynchrony on tri-plane TDI have significantly higher values of histogram bandwidth and phase SD derived from phase analysis with GMPS (histogram bandwidth: 186°±52° versus 74°±24°, p<0.0001) and phase SD: 55.3°±13.6° versus 25.1°±7.6° (p<0.0001).
CRT is now considered an important therapeutic option in the treatment of patients with end-stage heart failure [
1]. Although encouraging beneficial effects have been reported, including improvement in LVEF and reduction in heart failure symptoms, it has also been demonstrated that up to 30% of patients do not have a favorable response to CRT. The presence of LV dyssynchrony is considered a key issue in the identification of potential responders to CRT [
3‐
6]. Echocardiography and in particular TDI have been extensively used to assess LV dyssynchrony. Several parameters derived from myocardial velocity curves of different LV segments have been proposed to quantify LV dyssynchrony and predict response to CRT [
3‐
8]. Yu and coworkers described a model (derived from 2D TDI data) to quantify global LV dyssynchrony using Ts-SD of 12 LV segments [
6‐
8]. The authors reported a cut-off value >32.6 ms to distinguish between responders and non-responders [
8] and a cut-off value >34.4 ms as the most powerful predictor of LV reverse remodeling [
7]. In this study LV dyssynchrony was evaluated by Ts-SD from tri-plane TDI and compared with LV dyssynchrony assessment with phase analysis by GMPS. The tri-plane TDI technique avoids the problem of heart rate variability since simultaneous acquisition of the three apical views is possible; in the present study a cut-off value ≥ 33 ms was used to define substantial LV dyssynchrony on tri-plane TDI.
Information on cardiac dyssynchrony can also be derived from nuclear imaging. Kerwin et al. [
13] evaluated interventricular dyssynchrony in 13 heart failure patients using multi-gated equilibrium blood pool scintigraphy and phase analysis. Patients were imaged during biventricular pacing and in sinus rhythm. During biventricular pacing, a significant improvement in interventricular synchrony was observed. Moreover, an improvement in LVEF was reported for all 13 patients during biventricular pacing (17.2±7.9% to 22.5±8.3%,
p<0.0001), and the increase in LVEF correlated significantly with the improvement in interventricular synchrony (
r=0.86;
p<0.001). Fauchier et al. [
14] used equilibrium radionuclide angiography and phase analysis to evaluate the prognostic value of interventricular and intraventricular dyssynchrony in 103 patients with idiopathic dilated cardiomyopathy. Phase images were generated from the scintigraphic data, and mean phase angles and SDs were calculated for the right and left ventricle. During a follow-up period of 27±23 months, 18 major cardiac events occurred. Multivariate analysis revealed that LV intraventricular dyssynchrony and elevated pulmonary capillary wedge pressure were the only independent predictors of cardiac events.
GMPS is currently used in patients with heart failure to exclude ischemia and/or viability before referring for CRT implantation and to assess total scar burden in patients with ischemic cardiomyopathy [
11,
12]. Indeed, various studies have shown that the presence of severe resting perfusion defects, as assessed with GMPS, limits the response to CRT [
15‐
17]. Recently, Chen et al. [
9] developed with GMPS a count-based method to extract phase information from the regional LV count changes throughout the cardiac cycle. The phase information is related to the regional onset of mechanical contraction of the LV (phase analysis) and provides information on the synchronicity of the LV contraction. The authors assessed in 90 normal individuals the normal range for four quantitative indices that can be used as markers of LV dyssynchrony (histogram bandwidth, phase SD, histogram skewness and histogram kurtosis) [
9]. Recently, these four GMPS indices have been compared with LV dyssynchrony assessment by TDI in 75 patients with severe heart failure. It was shown that among the four quantitative indices of phase analysis, the variables histogram bandwidth and phase SD correlated best with LV dyssynchrony as assessed by TDI [
10]. The current study involved a different patient subset and provides further support that phase analysis with GMPS can be useful in the evaluation of LV dyssynchrony.
The value of GMPS to assess LV dyssynchrony has been analyzed, and the indices derived from phase analysis were compared with Ts-SD measured by tri-plane TDI. It was shown that histogram bandwidth and phase SD correlated well with Ts-SD as evaluated by tri-plane TDI (histogram bandwidth: r=0.77 and phase SD: r=0.74). In addition, significantly higher values for histogram bandwidth and phase SD were observed in patients with substantial LV dyssynchrony on tri-plane TDI compared with patients without substantial LV dyssynchrony on tri-plane TDI.
Limitations
In the present study, follow-up data after CRT implantation were not available. Therefore, the value of phase analysis to predict response to CRT could not be determined. Furthermore, GMPS may be less suitable for repeated analysis during the follow-up after CRT implantation, due to the radiation burden of the technique.
Acknowledgements
This work was financially supported by:
The Netherlands Heart Foundation, The Hague, The Netherlands, grant number 2002B109.
The European Society of Cardiology, Research Fellowship