Influence of the atrio-ventricular delay optimization on the intra left ventricular delay in cardiac resynchronization therapy

Background Cardiac Resynchronization Therapy (CRT) leads to a reduction of left-ventricular dyssynchrony and an acute and sustained hemodynamic improvement in patients with chronic heart failure. Furthermore, an optimized AV-delay leads to an improved myocardial performance in pacemaker patients. The focus of this study is to investigate the acute effect of an optimized AV-delay on parameters of dyssynchrony in CRT patients. Method 11 chronic heart failure patients with CRT who were on stable medication were included in this study. The optimal AV-delay was defined according to the method of Ismer (mitral inflow and trans-oesophageal lead). Dyssynchrony was assessed echocardiographically at three different settings: AVDOPT; AVDOPT-50 ms and AVDOPT+50 ms. Echocardiographic assessment included 2D- and M-mode echo for the assessment of volumes and hemodynamic parameters (CI, SV) and LVEF and tissue Doppler echo (strain, strain rate, Tissue Synchronisation Imaging (TSI) and myocardial velocities in the basal segments) Results The AVDOPT in the VDD mode (atrially triggered) was 105.5 ± 38.1 ms and the AVDOPT in the DDD mode (atrially paced) was 186.9 ± 52.9 ms. Intra-individually, the highest LVEF was measured at AVDOPT. The LVEF at AVDOPT was significantly higher than in the AVDOPT-50setting (p = 0.03). However, none of the parameters of dyssynchrony changed significantly in the three settings. Conclusion An optimized AV delay in CRT patients acutely leads to an improved systolic left ventricular ejection fraction without improving dyssynchrony.


Background
Asynchronous myocardial contraction in heart failure is associated with poor prognosis. Recent studies have shown an acute and sustained hemodynamic improve-ment after biventricular pacing (BVP), reversal of LVremodelling, an increased quality of life, a reduction of symptoms of heart failure, and an improvement of exercise tolerance [1][2][3][4][5][6][7].
The optimization of the AV delay in DDD pacemaker patients is generally recommended and is performed in clinical practice. A variety of invasive and non-invasive methods were assessed in the past [8][9][10][11][12][13][14][15]. Recent studies have shown that also in CRT patients, invasively (dP/dt) [16][17][18][19] and non-invasively measured hemodynamic parameters (stroke volume) [20,21] are modified according to the programmed AV delay. A hemodynamically optimal AV delay can be defined.
Ismer's method of AV delay optimization [22] is validated for biventricular as well as right ventricular DDD pacing.
Tissue Doppler Imaging (TDI) is an evaluated tool in clinical practice to identify myocardial dyssynchrony. TDI (including strain and strain rate) imaging measures regional wall motion velocities and can accurately quantify regional left ventricular function [24].
Strain measures compression and distension of myocardial segments ("deformation imaging") and strain rate imaging expresses strain changes per time interval [25]. TSI (Tissue Synchronization Imaging) utilizes color-coded time-to-peak tissue Doppler velocities and visualizes segments of dyssynchrony in real-time by superimposing these temporal motion data on 2D echo images. [26,27].
These new techniques could potentially improve patient selection and guidance of implantation and programming of the devices for BVP. There is a variety of methods to determine dyssynchrony as summarized elsewhere [28].

Patients
11 chronic heart failure patients of our clinic were included in this study. All patients had a biventricular ICD (pre-implantation NYHA III-IV, EF < 35%, QRS width > 120 ms). Clinical characteristics are demonstrated in Table 1. Patient exclusion criteria were as follows: atrial fibrillation, pacemaker malfunction and oesophageal diseases, NYHA IV, prosthetic mitral valve replacement.

AV delay: components and optimization
For the AV delay optimization we used the method proposed by Ismer et al [22].
This approach needs the placement of a bi-polar oesophageal electrode to provide a filtered left-atrial electrogram (LAE). We applied a 5F oesophagus electrode (Osypka TO2/5F, order no. TA12991101, Rheinfelden, Germany). Filtered oesophageal electrogram and telemetric real-time pacemaker markers provided by the programmer's analogue output were superimposed on the display of transmitral flow velocity on the Doppler-echo system ( Figure  1). The simultaneous recording of transmitral flow, the left atrial oesophageal electrogram and the real-time sense-event markers, allow determining the components of the optimal AV delay (Table 2, Figure 1 and 2).
Based on these measurements, optimal AV delays were calculated for VDD (atrial-triggered) and DDD (atrialpaced) mode using the equations: AVD OPT VDD = MA-LA + LA-EAC long -Sv-EAC short and AVD OPT DDD = SA-LA + LA-EAC long -Sv-EAC short
Echocardiography was performed on the Vivid 5 and Vivid 7 Dimension (GE Vingmed Ultrasound, Horton, Norway) machines. The TDI and strain analysis were performed in an off-line work station. The LVEF was assessed by area-length method in the apical four chamber view. The CI and the SV were calculated from the systolic velocities measured by PW-Doppler in the aortic outflow tract. Strain rate, tissue Doppler velocities were measured in the basal segments of the apical four-, three-and two-chamber views.

Statistics
Values are expressed as mean ± standard deviation (SD). Groups were compared by parametric or non-parametric tests (t-tests and Wilcoxon-Mann-Whitney tests, respectively). Statistical significance was assumed at a value of P < 0.05. Statistical analysis was performed with the SPSS 12 software package (SPSS; Chicago, Ill, USA).

Optimal AV delay
In all patients, we could define an optimal AV delay in the VDD and the DDD modes respectively. The AVD OPT in VDD mode was 105.5 ± 38.1 ms and the AVD OPT in the DDD pacing mode was 186.9 ± 52.9 ms. The results are summarized in Table 3. As expected, the mean optimal AV delay was lower in the VDD than in the DDD mode. Echocardiography was performed subsequently under three pacemaker settings: AVD OPT , AVD OPT -50, AVD OPT +50. All patients had continuous biventricular stimulation even under AVD OPT +50.

2D and TDI echocardiography
The LVEF with AVD OPT was 28% (± 12%), with an AVD OPT -50 20% (± 7%, p= 0.03 compared to AVD OPT ), with an AVD OPT +50 23% (± 7%, p = 0.11 compared to AVD OPT ). The heart rate did not change significantly in the different settings (AVD OPT : 65,4/min, AVD OPT -50: 65,6/ min, AVD OPT +50: 65,8 ms). The hemodynamics (SVI, CI, LVEF) and the TDI derived data are listed in Table 4. There was no significant difference of the amount of segments with dyssynchrony in TSI in the three settings. The maxi-mal delay in the basal segments in the apical two-, threeand four-chamber views measured by TSI and strain did not differ in the AVD OPT , AVD OPT +50 and AVD OPT -50 setting.

Optimal AV delay
To date, Ismer's method for the optimal AV delay was applied to patients with DDD pacemakers and normal left ventricular function [22,23]. This is the first study to assess the optimal AV delay by Ismer's method in patients with reduced left ventricular function. In our CRT patients, an optimal AV delay according to Ismer's method could be defined. This is the only method that allows separate measurement of the three AV-delay components: i.e., the pacemaker-related interatrial conduction time, the left-atrial electromechanical action, and the leftventricular latency period. The benefits of this method, however, are offset by the necessity for placement of an oesophageal electrode. This requirement explains why only a few medical centres have applied this method in clinical practice and in most cases for purposes of scientific investigation only.
Our results concerning the AVD OPT in the VDD mode (105.5 ± 38.1 ms) are in agreement with the results of other studies on AVD OPT in CRT patients: Butter [16] determined an AVD OPT of 100 ms in 30 patients, Auricchio [17] an AVD OPT of 112 ± 33 ms in 41 patients and Kass [18] an AVD OPT of 125 ± 49 ms. A study that was recently published by Porciani [29] found an AVD OPT during simultaneous biventricular pacing of 97 + 27 ms.
In the literature, there are no published data on AVD OPT in DDD mode. Therefore, our AVD OPT in DDD mode of 186.9 ± 52.9 ms cannot be compared to other studies.

Hemodynamics
Intra-individually, the patients had the best LVEF under optimal AV-delay compared to the +50 and -50 ms settings. The LVEF is significantly higher in the AVD OPT setting than in the AVD OPT -50 setting. Obviously the formation of "cannon waves" seen with a shorter AV interval (AVD OPT -50) had a more negative hemodynamic effect than the diastolic mitral regurgitation seen with longer AV delays (AVD OPT +50). The hemodynamically unfavourable effects of "cannon waves" are described since the beginning of pacemaker therapy and are also termed "pacemaker syndrome". It is generally accepted that an adequate pacemaker programming can avoid this [30]. Toda et al. [31] could show in his studies that the mean LVEF in AVD OPT is higher than in prolonged AV delays. However, he found no significant difference.

Dyssynchrony
Changes of dyssynchrony can be seen immediately, as seen in studies that have examined on/off comparisons in CRT patients [32]. However, an optimized AV interval does not change the markers of dyssynchrony. The reason for the improved hemodynamic situation under AVD OPT seems to be the better left ventricular filling and not the altered dyssynchrony.

Limitations
This study included only a small number of patients. There was no follow-up examination of the patients.

Conclusion
This study confirmed that an optimized AV delay improves the left ventricular ejection fraction. Acutely, the optimized AV delay does not influence left ventricular dyssynchrony. Whether a long-term AVD OPT leads to changes in left ventricular dyssynchrony via an improved LVEF and reverse remodelling can only be speculated. This has to be addressed in future studies with a long-term observation interval.

Competing interests
The author(s) declare that they have no competing interests.