Europace Advance Access originally published online on July 8, 2008
Europace 2008 10(8):901-906; doi:10.1093/europace/eun177
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REVIEW
Ventricular optimization of biventricular pacing: a systematic review
University Department of Medicine, City Hospital, Birmingham B18 7QH, UK
Manuscript submitted 25 March 2008. Accepted after revision 10 June 2008.
* Corresponding author: Department of Cardiovascular Medicine, University Hospital Birmingham, Birmingham B15 2TT, UK. Tel: +44 121 507 5080. E-mail address: hsern{at}doctors.net.uk
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Abstract |
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Biventricular pacing has been shown to improve the overall clinical outcomes in patients with systolic heart failure and ventricular conduction delay on electrocardiogram. As correction of ventricular dyssynchrony is the putative mechanism of benefit, biventricular pacing is also termed as cardiac resynchronization therapy. The development of separate programmability of right and left ventricular output has led to a growing number of reports on the potential benefit of optimization of cardiac resynchronization by sequential biventricular pacing with different techniques and endpoints. This systematic review summarizes the current data for the optimization of sequential (V–V delay) compared with (default) simultaneous biventricular pacing in heart failure.
Key Words: Biventricular pacing, Systolic heart failure, Optimization, Cardiac resynchronization
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Introduction |
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Approximately a third of patients with systolic heart failure exhibit ventricular conduction delay on the surface electrocardiogram (ECG).1
Ventricular conduction delay and left bundle branch block, in particular, are associated with delay between the activation of the left ventricular (LV) and right ventricular (RV) contraction (the so-called ‘inter-ventricular dyssynchrony’) and also between different segments of the LV, typically with delayed activation of the inferior and lateral aspects of the LV (the so-called ‘intra-ventricular dyssynchrony’).
In the setting of ventricular dyssynchrony, shortening at the site of early activation generates low pressure with no effective ejection and is thus essentially wasted work; whereas contraction at the region of delayed activation occurs at higher stress because the region has already developed tension, and it is also characterized by wasted work because the territory that was activated earlier may now undergo paradoxical stretch. The consequent dyssynchronous inter- and intra-ventricular contraction results in reduction in LV filling time, regional and global LV ejection fraction (LVEF), and dP/dt and exacerbates diastolic mitral regurgitation. These haemodynamic changes may explain the adverse prognosis associated with ventricular conduction delay in patients with systolic heart failure.2–4
Biventricular pacing was introduced to overcome the adverse consequences of dyssynchronous ventricular contraction by pre-exciting regions of delayed activation and shortening ventricular activation, thereby resynchronizing ventricular contraction.5 Hence, biventricular pacing is also termed ‘cardiac resynchronization therapy’ (CRT). Randomized trials of biventricular pacing in patients with systolic heart failure to date have used ventricular conduction delay on ECG to identify patients with ventricular dyssynchrony. Although these studies showed significantly improved clinical outcomes with biventricular pacing when compared with placebo (Table 1),6–8 
30% of the patients did not show symptomatic improvement, and the placebo-subtracted improvement in functional capacity may even be as low as 15–30% in these studies.
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Similarly, a large proportion of patients do not show echocardiographic improvement in LV dimension and/or function in response to CRT.9
–11 The improvement in the LV size and function (‘reverse remodelling’) has been reported to be a key predictor of mortality in patients with heart failure treated with CRT. For example, Yu et al.12 used a threshold of 10% reduction in the LV end-systolic volume to define responders to CRT and reported 30% mortality in <2 years among non-responders compared with 7% among CRT responders. Notably, symptomatic improvement was not associated with better survival.
The high proportion of CRT non-responders and the adverse prognosis of these patients have prompted the current search for predictors of response and techniques to optimize ventricular resynchronization after device implantation. Although pacing from the site that produces the greatest decrease in QRS duration may be intuitive, the correlation between decrease in QRS duration and haemodynamic effect has been poor, as haemodynamic improvement can occur without shortening of the QRS duration.13 In contrast, the presence of ventricular dyssynchrony defined by various echocardiographic measurements appears to predict response to CRT, with the extent of improvement in the systolic function related to the degree of ventricular dyssynchrony in some studies.14,15 These data are consistent with the putative mechanism of benefit of biventricular pacing and provide the basis for individualized ‘optimization’ of biventricular pacing to maximize the benefit of CRT.
Until recently, available devices only allowed simultaneous stimulation of the RV and LV, or stimulation of the RV or LV alone. The current generation of devices is capable of a separate programmable activation delay between the RV and LV (V–V timing) and thus allows individualization of the depolarization vector. The alteration of the V–V delay has been proposed as a method of compensating for a suboptimal LV lead position by altering the activation front.16 However, methods and modalities used for ‘optimization’ of biventricular pacing devices are many, and the endpoints are variable. The aim of this systematic review is to summarize the published studies of ventricular optimization with biventricular pacemakers.
Search strategy
MEDLINE and EMBASE were searched using the terms ‘resynchronis(z)ation’, ‘optimis(z)ation’, ‘sequential’, and ‘heart failure’ to July of 2007. Abstracts were reviewed and articles comparing optimized (or sequential) and simultaneous biventricular pacing were included. We excluded animal studies, abstracts, and individual case reports. Articles relating specifically to atrioventricular optimization or comparisons of biventricular and univentricular pacing17,18 were also excluded. References from the relevant articles were reviewed and related articles were identified. We identified 70 articles, from which 18 were selected for detailed review.
Echocardiographic optimization of biventricular pacing
Sogaard et al.19 were the first to demonstrate the additional benefit of optimization over ‘default’ simultaneous biventricular pacing using three-dimensional echocardiography and tissue Doppler imaging. In this study, which used tissue Doppler to assess dyssynchrony and three-dimensional echocardiography to follow the changes in LV volume, there was an immediate reduction in the LV dyssynchrony, and an increase in the LVEF (22 ± 6 to 30 ± 5%) was demonstrated with simultaneous biventricular pacing, which was further improved by optimization (to 34 ± 6%). Ventricular optimization was also shown to reduce many functional abnormalities intrinsic to the delayed and abnormal pattern of ventricular activation—reduction in mitral regurgitation, ventricular dyssynchrony, and increase in diastolic ventricular filling time and cardiac output.20 However, there is considerable variability between patients as to whether RV or LV pre-excitation is better. In the study by Bordachar et al.,20 LV pre-activation was superior in 25 subjects, RV in 10, and simultaneous biventricular pacing in 6 patients.
Other echocardiographic parameters used for the optimization of biventricular pacing include inter- and intra-ventricular dyssynchrony (by time to aortic and pulmonary outflow on pulse wave Doppler and time to peak systolic velocity on tissue Doppler imaging),21–23 aortic velocity time integral (VTi) (as a measure of cardiac output),23 and myocardial performance index (derived from filling and ejection times on pulse wave Doppler).24,25 The majority of these studies showed greater improvement in ventricular dyssynchrony, cardiac output, and LVEF with optimized when compared with simultaneous biventricular pacing (Table 2). However, in a post hoc analysis of the InSync III study, Leon et al.26 reported no significant difference in the New York Heart Association (NYHA) class or quality of life improvement with biventricular pacing optimized by Doppler echocardiographic-derived stroke volume compared with the simultaneous biventricular pacing and control arms from the MIRACLE study, although there was a modest improvement in the 6 min walk distance.
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Invasive optimization of biventricular pacing
Maximizing LV dP/dt, as a measure of contractility, has been the most widely used method for invasive optimization of biventricular pacing. These studies used micromanometer catheters positioned in the LV to measure dP/dt and showed incremental haemodynamic benefit with optimization over default simultaneous biventricular pacing in the majority of the patients (Table 3).27
–30
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Other methods of ventricular optimization
Other reported methods of optimizing biventricular pacing include the use of radionuclide ventriculography (to measure LVEF and dyssynchrony),31
impedance cardiography (to measure cardiac output),32 and digital photoplethysmography.33 The latter measures beat-to-beat finger arterial blood pressure using a cuff placed around the finger with a built-in photoelectric plethymography and volume-clamp circuit. The relative change in mean systolic blood pressure 10 beats immediately after transition is compared against the 10 beats before for different V–V delays. The mean systolic blood pressure for the 10 beats immediately after transition is selected as it is likely to reflect changes in the cardiac function before peripheral responses occur. Using these methods, optimized biventricular pacing was shown to further improve dyssynchrony, LVEF, cardiac output, and systolic blood pressure in the majority of the patients, compared with simultaneous biventricular pacing.
More recently, the intra-cardiac electrogram from the RV and LV has been used to optimize V–V delay.34 This method (now incorporated into commercial devices) was shown to have a close correlation with stroke volume (derived from aortic VTi on echocardiography).
Randomized trials of optimized vs. simultaneous biventricular pacing
There are two randomized trials comparing optimized sequential and ‘default’ simultaneous biventricular pacing. The Resynchronization for the HaemodYnamic Treatment for Heart failure Management II Implantable Cardioverter Defibrillator (RHYTHM II ICD) study35 included 126 patients successfully implanted with biventricular pacemakers and used conventional Doppler echocardiographic measurements to assess inter-ventricular dyssynchrony and optimize biventricular pacing (stroke volume derived from aortic VTi). The RV was stimulated first in 30 patients (34.1%), the left in 31 patients (35.3%), and simultaneous biventricular pacing was found to be optimal in 25 patients (28.4%). There was no significant difference in the 6 min walk distance and NYHA class at the end of the study (6 months) between the two groups. However, exercise capacity deteriorated (defined as >10 m reduction in 6 min walk distance) in 16.2% of the patients randomized to optimized biventricular pacing, compared with 3.7% in the simultaneous biventricular pacing when analysed by intention-to-treat, and almost 21% compared with 5% on per-treatment actually received. Of note, the AV interval was not optimized following optimization of the V–V interval.
The Device Evaluation of CONTAK RENEWAL 2 and EASYTRAK 2: Assessment of Safety and Effectiveness in Heart Failure (DECREASE-HF) trial36 is a three-arm randomized, double-blind comparison of LV pace only, simultaneous and optimized sequential biventricular pacing (1:1:1 ratio). This study included 306 patients and optimization of the ventricular intervals was derived from the electrical delay between the RV and LV (based on intra-cardiac electrograms). Patients were excluded if the Expert Ease device algorithm recommended simultaneous biventricular pacing. The V–V timing was programmed according to an algorithm that takes into account the intrinsic inter-ventricular delay measured from the intra-cardiac electrogram at the time of device implantation for other patients randomized to the optimized sequential pacing arm. This algorithm was derived from acute haemodynamic data from unpublished patient data from the PAcing THerapies for Congestive Heart Failure II (PATH-CHF) study. The DECREASE-HF study reported significant reductions in LV end-systolic volumes at 6 months in all the three groups (–8.6 + 24.8, –12.2 + 20.7, and –16.5 + 24.0% in the LV pacing, sequential, and simultaneous biventricular pacing groups, respectively), although the difference between the three groups did not reach statistical significance (P= 0.09). There was no significant difference in other LV dimensions and function at 6 months. There was also no significant difference in peak VO2 between the three groups, although the full report has yet to be published (Table 4).
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Additional value of atrioventricular optimization
In this article, we have summarized the published studies on ventricular optimization of biventricular pacemaker. In an acute haemodynamic study of 27 patients, Auricchio et al.37
demonstrated improvement in haemodynamic measurements with optimization of AV delay, which suggests that optimization of LV filling may further improve the cardiac output by adjusting the AV delay. This may be particularly relevant in the setting of biventricular pacing, which alters (shortens) the pre-aortic ejection and LV filling intervals.38 Hence, further improvement in LV filling and cardiac output with optimization of the AV interval following V–V optimization is physiologically plausible. It is not clear if the acute haemodynamic benefit of AV interval optimization in addition to V-V interval optimization will translate into clinically significant functional improvement. |
Conclusion |
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Current biventricular devices allow separate programming of LV and RV stimulation, with the aim of ‘optimizing’ the depolarization vector to overcome the adverse haemodynamic effects associated with ventricular conduction delay. However, the data supporting ventricular optimization of biventricular pacing are limited to predominantly small, single centre, non-randomized, short-term studies employing various surrogate endpoints. The two randomized studies todate have failed to demonstrate any significant improvement in functional status, LV dimensions, and quality of life, which may be due to inadequate power to detect these changes (especially as up to a third of patients may be optimized to simultaneous biventricular pacing), or the technique used for optimization. Whether optimization based on newer echocardiographic techniques, such as speckle tracking, strain analysis (tissue synchronization imaging), and three-dimensional/four-dimensional echocardiography can improve outcome remains to be studied. In addition, dynamic optimization with exercise may yield additional haemodynamic benefit as ventricular dyssynchrony may alter significantly with exercise in over 50% of the patients with heart failure.39
,40 Whether the use of these newer techniques will translate into better response to optimized biventricular pacing has yet to be determined. Conflict of interest: none declared.
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