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European Journal of Heart Failure 2004 6(5):619-625; doi:10.1016/j.ejheart.2004.05.005
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© 2004 European Society of Cardiology

Guiding and optimization of resynchronization therapy with dynamic three-dimensional echocardiography and segmental volume–time curves: a feasibility study

Boudewijn J. Krenning, Tamas Szili-Torok, Marco M. Voormolen, Dominic A.M.J. Theuns, Luc J. Jordaens, Charles T. Lancée, Nico de Jong, Anton F.W. van der Steen, Folkert J. Ten Cate and Jos R.T.C. Roelandt*

Erasmus Medical Center, Thoraxcenter Room H536, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands

* Corresponding author. Tel.: +31-10-4635312; Fax: +31-10-4362995. j.r.t.c.roelandt{at}erasmusmc.nl


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Objective: To assess a new approach for guiding and hemodynamic optimization of resynchronization therapy, using three-dimensional (3D) transthoracic echocardiography.

Background: Resynchronization therapy for heart failure provides the greatest hemodynamic benefit when applied to the most delayed left ventricular (LV) site. Currently, the ideal LV pacing site is selected according to acute invasive hemodynamic assessment and/or tissue Doppler imaging.

Methods: A total of 16 patients with advanced heart failure and an implanted biventricular pacemaker were included in this study. Transthoracic apical LV images at equidistant intervals were obtained using a prototype, fast-rotating second harmonic transducer to reconstruct 3D LV datasets during sinus rhythm (SR), right ventricular (RV) apical and biventricular pacing mode. A semi-automated contour analysis system (4D LV analysis, TomTec, Germany) was used for segmental wall motion analysis and identification of the most delayed contracting segment and calculation of global LV function.

Results: Data acquisition duration was 10 s and analyzable 3D images were obtained in 12 patients. Of these patients, data during SR were available in 9 and during biventricular pacing in 11. The greatest contraction delay during SR was found in the anterior and antero-septal segments in five of nine patients. Biventricular pacing resulted in reduction of the contraction delay in seven of eight patients. The global LV function did not change significantly.

Conclusion: 3D echocardiography with appropriate analytic software allows detection of the most delayed LV contracting segment and can be used to select the optimal pacing site during resynchronization therapy.

Key Words: Resynchronization therapy • Three-dimensional echocardiography • Automated border detection

Received October 23, 2003; Revised May 3, 2004; Accepted May 12, 2004


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Delayed intraventricular depolarization leads to dyssynchrony of ventricular contraction and worsens left ventricle (LV) dysfunction [1–4]. Resynchronization by simultaneous electrical stimulation of both ventricles significantly improves hemodynamics, resulting in increased exercise tolerance and hence quality of life [5–12]. Reduction in morbidity and mortality awaits confirmation from ongoing large-scale studies [5,13]. Recent data indicate that biventricular pacing provides the greatest hemodynamic benefit when applied to the LV segment with the most delayed contraction [14]. Tissue Doppler imaging (TDI) is currently used to identify the most delayed contraction site before the implantation of a resynchronization device [14–16]. This method cannot be used online and the assessment of the hemodynamic effects requires additional studies. It has been demonstrated in previous studies that volume–time curves (VTCs) provide quantitative information on LV performance [17,18]. The aim of the present study was to test the feasibility of 3D echocardiographic VTCs for determining the optimal pacing site. This allows simultaneous hemodynamic evaluation by measuring global LV function.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Study patient
We studied 16 patients with severe heart failure and a permanent biventricular pacemaker. All patients gave informed consent. Patient characteristics are listed in Table 1. The diagnosis of dilated cardiomyopathy was established according to the classification of cardiomyopathy published previously [19]. Criteria for biventricular pacing were severe heart failure (NYHA II–IV) and dilated cardiomyopathy associated with complete left bundle branch block and a QRS duration of >125 ms. The LV pacing lead was positioned in the coronary sinus and the right atrial and right ventricular (RV) leads in standard locations.


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  		Table 1 Patient characteristics and results for contraction delay measurements

 
Three acquisitions for 3D reconstruction were performed as follows: The first acquisition was performed in the biventricular pacing mode and the second after the pacemaker was reprogrammed for RV pacing. In patients with intact atrio-ventricular conduction and sinus rhythm (SR), the pacemaker was reprogrammed in order to perform acquisitions during SR. In every patient, the pacemaker was finally reset to the original settings. Acquisitions were performed 5 min after the pacing mode was switched. Data analysis was performed off-line for this feasibility study.

2.2. Image acquisition
We used a prototype transthoracic, fast-rotating ultrasound transducer for 3D echocardiographic image acquisition [20] (Fig. 1), which is connected to a commercially available ultrasound system (GE Vingmed Vivid FiVe, Horton, Norway). The 64-element transducer array has a center frequency of 3 MHz and second harmonic capabilities [21]. It continuously rotates inside the transducer assembly at a maximum speed of 8 revolutions/s. The frame rate of the ultrasound system is 100 frames per second. The typical acquisition time is 10 s during a single end-expiratory breath hold. Patients were studied in the left lateral decubitus position with the transducer in the apical position and the image plane rotating around the LV long axis. The depth setting was adjusted to visualize the entire LV and part of the left atrium. Gain and power settings were optimised for endocardial border visualization. The ECG signal was simultaneously recorded for 3D reconstruction.


Figure 1
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  		Fig. 1 Latest prototype of the continuous fast-rotating transducer.

 
2.3. Image processing
Data are transferred via a network connection to a dedicated workstation for processing and analysis. With self-developed software, using MatLab (The MathWorks, Natick, MA, USA), the original 2D images are post-processed by placing them in their correct spatial and temporal (ECG reference) position using multi beat data fusion [22]. The cardiac cycle is divided in 12 equal intervals, which allows to create 12 3D datasets. Due to the continuous rotation of the transducer array, the original 2D images have a curved shape. However, these are not suited for automated contour analysis with currently available software. Therefore, 20 equidistant plane cross-sectional images (9° interval) are re-sampled from these 12 datasets and used for further analysis.

2.4. Image analysis
All the 20 cross-sectional images re-sampled from each of the 12 datasets are subsequently imported into the TomTec® 4D LV-analysis software (TomTec® Imaging Systems, Germany) and displayed (Fig. 2). Their orientation in 3D space is determined by marking the mitral valve, aortic root and apex as landmarks. An elliptical model is placed over one of the images of each cross-sectional position. After this, the software automatically performs endocardial border detection in all images of each cross-sectional position in the 12 datasets. A spatio-temporal spline model is used to generate smooth contours for both the temporal and spatial domain. The long axis of the ventricle is calculated from the center of the mitral annulus to the most distant point in the ventricle, which is the apex.


Figure 2
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  		Fig. 2 From each dynamic 3D dataset, up to 20 cross-sectional images can be selected. The orientation of each cross-section is shown.

 
Two experienced investigators verified and corrected the results from the automated border detection where necessary. This was done blinded, without knowledge of the pacing mode for each analysis. The papillary muscles within the LV cavity are not taken into account for the definition of the contour. After completion of the endocardial border tracing, the program performs a dynamic surface rendered endocardial reconstruction of the LV (Fig. 3A). For each pacing mode, a VTC is plotted from which global LV end-diastolic volume (LVEDV), end-systolic volume (LVESV) and ejection fraction (EF) are calculated applying Gaussian quadrature formulas.


Figure 3
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  		Fig. 3 Three-dimensional reconstruction of the LV (A) and bulls-eye view according to which the endocardial surface is subdivided in 16 colour-coded segments (B).

 
The LV endocardial surface is subdivided in 16 segments, which are colour coded for orientation (Fig. 3B). A segmental volume represents the pyramidal volume of a segment to the center of gravity (Fig. 4). The volume change of a segment over the cardiac cycle is plotted in a VTC (Fig. 5), in which time is defined as percentage of the total cardiac cycle. The end-systolic moment, at which a segment has completed maximal myocardial contraction, is represented by the nadir of the segmental volume curve. This moment was extracted from the VTC for every segment in every pacing mode. The difference in time to maximal myocardial contraction between segments was used to assess regional mechanical delay and a measure of segmental dyssynergy. From the VTC that represents segmental volume changes in SR, the first contracting segment and the most delayed segment were identified. The delay in contraction was calculated as the difference in time to maximal contraction between these segments and is expressed as percentage of the total cardiac cycle. Using the RR-interval, this was re-calculated in milliseconds. When a segment is hypo- or akinetic, which we defined as a segmental volume change during any part of the cardiac cycle of less then 20%, the segment is not included. In both biventricular and RV pacing mode, the most delayed segment is determined and the delay between this segment and the first contracting segment calculated.


Figure 4
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  		Fig. 4 A segmental volume represents the pyramidal volume of a segment to the center of gravity. The long axis of the ventricle is calculated from the center of the mitral annulus to the apex.

 


Figure 5
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  		Fig. 5 Example of volume–time curves of four different segments. During sinus rhythm, each segment completes myocardial contraction at a different moment (indicated with an arrow for every segment), causing LV dyssynchrony. From the various delays, the largest delay is shown with a dotted line (A). During biventricular pacing, synchrony in segmental contraction is present (B).

 
2.5. Statistical analysis
Data are presented as mean±S.D. 3D measurements of LV volume were calculated by the analysis software after completion of the endocardial border tracing. To assess accuracy, analysis of VTCs was performed by two observers and analyzed by linear regression and a limits-of-agreement analysis, expressed as the mean difference and 2 S.D. of the difference between the measurements of the two observers. To determine whether the difference in the values between the two observers and between pacing modes was statistically significant, a paired t-test was performed. A probability level of p<0.05 was considered significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
Of the 16 patients, four were excluded from analysis because of inadequate echocardiographic image quality for faithful automated analysis. In 3 of the remaining 12 patients, no spontaneous sinus rhythm was present and therefore only acquisitions in biventricular and RV pacing mode were performed. In one patient, we did not perform an acquisition in biventricular pacing mode because of LV lead displacement.

3.1. Global LV function
The mean ejection fraction of all patients before implantation, by equilibrium radionuclide angiography, was 24±7%. During sinus rhythm, the mean LVEDV, LVESV and LVEF derived from the VTC were 294±85 ml, 230±94 ml and 24±12%, respectively. During RV pacing, these values were 291±97 ml, 225±81 ml and 23±6% and during biventricular pacing, 282±94 ml, 226±86 ml and 21±6%, respectively. No significant difference was present between these values.

3.2. Dyssynchrony
The mean heart rate during SR was 69±7 min–1, during biventricular pacing 73±9 min–1 and during RV pacing 74±9 min–1. No significant difference was present between these values. In six of eight patients, heart rate was less during SR compared to biventricular pacing. Table 1 shows the most delayed segment for every pacing mode and the delay between the first contracting and most delayed segment. The mean delay was 147±80 ms during SR, 103±34 ms during biventricular pacing (p<0.01; SR vs. biventricular pacing) and 158±78 ms during RV pacing (p<0.01; RV vs. biventricular pacing). In five of nine patients, the anterior or antero-septal segment was most delayed during SR. Biventricular pacing resulted in reduction of the contraction delay in seven patients, compared to SR. Also, in six patients, the contraction delay was less during biventricular pacing compared to RV pacing.

3.3. Interobserver agreement
Linear regression analysis indicated a good correlation (r=0.96) between measurements of delay in contraction between the first contracting segment and the most delayed site by two observers (Fig. 6). The standard error of estimate was 2.42%. The limits-of-agreement analysis demonstrated a small mean difference (0.03±2.50%) between measurements. A paired t-test indicated no significant mean difference between the two observers.


Figure 6
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  		Fig. 6 Regression analysis for measurement of delay between the two most delayed segments by two observers.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
This study shows that transthoracic dynamic 3D echocardiography performed with a fast-rotating transducer and combined with semi-automated contour analysis allows to identify LV segments with dyssynchrony together with hemodynamic evaluation. Our data indicate that this method is feasible for the selection of the optimal pacing site during resynchronization therapy.

4.1. Rationale for measuring mechanical delay in patients undergoing resynchronization device implantation
A delay in intraventricular conduction leads to dyssynchrony of ventricular contraction which can be corrected by biventricular pacing and subsequently improve hemodynamics. and consequently exercise tolerance and quality of life in patients with severe heart failure. Large-scale trials are ongoing to study long-term effects including morbidity and mortality [5,13,23]. However, a substantial proportion of the patients does not show improvement. This may be partly related to methodological reasons. Indeed, a prolonged QRS complex cannot quantify the degree of dyssynchrony. Clearly, biventricular pacing provides the most benefit when applied to the segment of the LV that is most delayed in contraction. Therefore pacing should be applied to this site but it should be noted that this site will not always be approachable during implantation. While long-term studies showed improvement of LVEF with biventricular pacing, this could not be observed in this study. Possibly, other regulating factors counterbalance the hemodynamic effect of changing pacemaker programming.

4.2. The role of improved imaging techniques to guide and evaluate biventricular pacing
Echocardiography has an important role in the evaluation of patients with mechanical dyssynchrony before biventricular pacemaker implantation [24,25]. Sogaard et al. [26] previously used 3D echocardiography for hemodynamic assessment in patients before and after biventricular pacemaker implantation. Currently, TDI is most often used as a guiding tool for the implantation [15,16] and is useful for identifying LV myocardial contraction dyssynchrony at discrete points in patients after ventricular resynchronization [14]. It is suggested that TDI analysis could serve in the future both as a tool for pre-implantation assessment and as a guide to select the most optimal pacing site. However, this approach requires a lengthy echo study and analysis before the implantation, while only the longitudinal function in the basal and mid-segments are studied. Also other diagnostic modalities, such as MRI [18] and gated-SPECT [27], can be used to create volume–time curves and assess regional wall motion. However, MRI cannot be used after device implantation because of its magnetic properties. 3D echocardiography with appropriate software for segmental wall motion analysis allows to determine dyssynchrony between all segments. Obviously, expressing the delay is an issue and requires standardization in the near future. Currently, several parameters are used for describing intra- and interventricular delays during the heart cycle. Using our method, the delay is expressed in relative units (as percentage of the total heart cycle). Actually, this method allows demonstration of shortening of the diastolic period when the heart rate increases. This may play a role in an adverse outcome of this patient population. This phenomenon is clearly demonstrated in Fig. 5. In this particular example, the heart rate in sinus rhythm was lower than in a paced rhythm. This results in relatively longer diastolic period. As the heart rate increases, the systolic period shortens relatively less than the diastolic period, meaning that the systolic periods are almost identical in absolute units (ms), but the diastolic periods become different. Additionally, the position of the RV lead has a significant impact on the LV conduction pattern. Therefore, the optimal technique should provide the information during the implantation procedure and additional hemodynamic data. This is possible with a fast-rotating ultrasound transducer and appropriate software for analysis.

4.3. Limitations of the study
We used prototype equipment for this proof-of-principle study requiring further refinements. The post-processing time to obtain a 3D dataset must be shortened to make this technique a practical guiding tool during the intervention. The semi-automated border detection algorithms are user-friendly, but manual interaction remains often a necessity. Real-time 3D echocardiography using a matrix transducer is also appropriate for acquisition of 3D datasets and optimisation of resynchronization therapy, using the same border detection and analytic software. Most experience is with the system developed at Duke University [28] (Volumetric Medical Imaging), which makes use of a sparse matrix phased array transducer to scan a 60°x60° pyramidal volume using parallel processing technology. More recently, Philips Medical Systems has introduced a matrix phased-array transducer with 3000 transmit-receive elements. Development of new border detection algorithms along with technological improvements of 3D echocardiography should be able to improve the accuracy of semi-automated border tracing and eventually provide automatic, even on-line, data analysis in the future.

This was not a prospective study and the patients studied had already their resynchronization device in place. Therefore, we could only study the feasibility of the method and whether dyssynchrony in segmental contraction could be measured.

During image acquisition, a 10-s breath hold was required. We did not find this inconvenient in our patient population with advanced heart failure.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
3D echocardiography is a feasible approach for determination of the most delayed LV site with the additional option to assess hemodynamic information, such as LVEDV, LVESV and EF. This preliminary data suggests that 3D echocardiography can be used for selection of the most optimal pacing site before and during resynchronization device implantation. Further studies with prospective study design are required to validate this data against other techniques, e.g. TDI.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 

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