Optimizing the Programation of Cardiac Resynchronization Therapy Devices in Patients With Heart Failure and Left Bundle Branch Block

Optimizing the Programation of Cardiac Resynchronization Therapy Devices in Patients With Heart Failure and Left Bundle Branch Block Bàrbara Vidal, MD, Marta Sitges, MD, PhD*, Alba Marigliano, MD, Victoria Delgado, MD, Ernesto Díaz-Infante, MD, Manel Azqueta, MD, David Tamborero, MSE, José María Tolosana, MD, Antonio Berruezo, MD, Félix Pérez-Villa, MD, PhD, Carles Paré, MD, PhD, Lluís Mont, MD, PhD, and Josep Brugada, MD, PhD This study was conducted to investigate the clinical impact of cardiac resynchronization device optimization. A series of 100 consecutive patients received cardiac resynchronization therapy. In the first 49 patients, an empirical atrioventricular delay of 120 ms was set, with simultaneous biventricular stimulation (interventricular [VV] interval ⴝ 0 ms). In the next 51 patients, systematic atrioventricular optimization was performed. VV optimization was also performed, selecting 1 VV delay: right or left ventricular preactivation (ⴙ30 or ⴚ30 ms) or simultaneous (VV interval ⴝ 0 ms), according to the best synchrony obtained by tissue Doppler– derived wall displacement. At follow-up, patients who were alive without cardiac transplantation and showed improvement of >10% in the distance walked in the 6-minute walking test were considered responders. There were no differences between the 2 groups at baseline. Left ventricular ejection fraction improved in the 2 groups, but left ventricular cardiac output improved only in the optimized group. At 6 months, patients with optimized devices walked slightly further in the 6-minute walking test (497 ⴞ 167 vs 393 ⴞ 123 m, p <0.01), with no differences in New York Heart Association functional class or quality of life compared with nonoptimized patients. Overall, the number of nonresponders were similar in the 2 groups (27% vs 23%, p ⴝ NS). In conclusion, the echocardiographic optimization of cardiac resynchronization devices provided a slight incremental clinical benefit at midterm follow-up. Simple and rapid methods to routinely optimize the devices are warranted. © 2007 Elsevier Inc. All rights reserved. (Am J Cardiol 2007;100: 1002–1006)

Although the clinical benefit of cardiac resynchronization therapy (CRT) has been proved in patients with advanced heart failure and left bundle branch block (LBBB),1,2 about 30% of patients do not respond to this treatment.3,4 To improve these results, CRT devices have been equipped to stimulate the 2 ventricles either simultaneously or sequentially, with a specific delay (the interventricular [VV] interval). Given that some ventricular segments have delayed conduction and contraction in patients with left ventricular (LV) dysfunction and LBBB, it is reasonable to think that LV preactivation may achieve better resynchronization.5,6 Furthermore, LV stimulation is currently performed from the epicardium, whereas the right ventricle is stimulated

from the endocardium. It has been shown that pacing from the epicardium results in a transmural delay.7,8 Lead positioning may also affect the transmission of the stimulus and the ventricular activation sequence, causing VV and intraventricular delays, which can in turn be modified with VV programming. Sequential biventricular stimulation has been shown to induce acute hemodynamic improvement compared with simultaneous biventricular pacing.5,7,9 –11 However, little is known about the clinical benefit of the optimization of the device.12 The main objective of our study was to evaluate whether the proportion of responders in the optimized group was higher than in the nonoptimized group. The secondary objective was to compare the extent of LV reverse remodeling in the 2 groups.

Thorax Clinic Institute, Hospital Clínic, Institut d’Investigacions Biomèdiques August Pi i Sunyer, University of Barcelona, Barcelona, Spain. Manuscript received March 14, 2007; revised manuscript received and accepted April 24, 2007. Drs. Vidal, Delgado, and Tolosana were supported by a postresidency award from Fundació Clínic, Barcelona, Spain. This study was supported in part by a grant from Fundación Española del Corazón 2006, Madrid, and by Grant FIS PI04/90069 from Fondo de Investigaciones Sanitarias, Madrid, Spain. *Corresponding author: Tel: 34-93-227-9305; fax: 34-93-451-41-48. E-mail address: [email protected] (M. Sitges).

Methods

0002-9149/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2007.04.046

In this observational cohort study, patients treated with simultaneous biventricular pacing devices were compared with patients who received CRT devices with sequential stimulation capability (and were therefore optimized). The nonoptimized group comprised 49 consecutive patients who received CRT devices without sequential activation capability. An empirical atrioventricular (AV) interval of 120 ms and a VV interval of 0 ms were set. The optimized group www.AJConline.org

Heart Failure/CRT Device Optimization

included 51 consecutive patients who underwent AV and VV interval optimization. The inclusion criteria for this study were (1) New York Heart Association functional class III or IV despite receiving optimal medical treatment for ⱖ2 weeks before device implantation, (2) LV ejection fraction ⱕ35%, (3) LV enddiastolic diameter ⬎55 mm, and (4) QRS width ⬎130 ms. Patients were excluded if (1) they had treatable cardiopathies, (2) heart transplantation was considered in ⬍6 months, or (3) they had co-morbidities that shortened life expectancy. The investigation conformed with the principles outlined in the Declaration of Helsinki, and the study protocol was accepted by our hospital’s ethics committee. Written informed consent was obtained from all patients. The study protocol included a baseline patient evaluation with the performance of transthoracic echocardiography (echocardiography off) to study LV anatomy, function, and synchrony and a clinical evaluation to determine New York Heart Association functional class, quality of life (using the Minnesota Living With Heart Failure Questionnaire), and 6-minute walking distance. The same echocardiographic protocol (echocardiography on) was repeated 24 to 72 hours after device implantation, and AV and VV intervals were optimized when the devices had the capability to stimulate sequentially. All patients were followed for 6 months, when new clinical and echocardiographic evaluations were performed. Patients were considered CRT clinical responders if at 6-month follow-up they were alive, had not required heart transplantation, and had improved the distance covered in the 6-minute walking test by ⱖ10%. Patients received pacemakers or defibrillators, according to clinical indications. Patients who received pacemakers without sequential stimulation capability were implanted with either a ContakHF or a Contak-Renewal (Guidant Corporation, Indianapolis, Indiana), and those assigned to devices with VV interval programming capability received a Contak TR or a Contak-Renewal II (Guidant Corporation). If a defibrillator was indicated, a Contak-Renewal II (Guidant Corporation) was implanted. One electrode was placed in the right atrium (if the patient was in sinus rhythm), another at the apex of the right ventricle, and the Easy Track (Guidant Corporation) electrode was implanted through the coronary sinus and advanced to a posterolateral branch. All LV leads were implanted transvenously. Standard Doppler echocardiography using a commercially available system (Sonos 5500; Philips Medical Systems, Andover, Massachusetts; or Vivid 7; GE-Vingmed Ultrasound AS, Horten, Norway) was performed just before initiating CRT, 24 to 72 hours after the implantation of the device and at 6-month follow-up. The same parameters were evaluated in each echocardiographic scan: LV dimensions were measured from M-mode echocardiography in the parasternal long-axis view, LV volumes and ejection fractions were quantified by Simpson’s method, and LV stroke volume was calculated using quantitative Doppler echocardiography, following the recommendations of the American Society of Echocardiography.13 Interventricular delay was calculated as the time difference between the preejective period at the pulmonary and aortic valves (from QRS to the onset of flow).14 Intraventricular LV asynchrony was evaluated with the time differ-

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ence in peak contraction of the septal and posterior walls of the left ventricle with M-mode scans from the parasternal view15; in the group of optimized devices, intraventricular LV synchrony was also assessed using tissue Doppler imaging (Tissue Tracking, EchoPac; GE Healthcare, Milwaukee, Wisconsin) by evaluating the synchronicity in the displacement of the lateral and septal walls and of the anterior and inferior walls in the 4- and 2-chamber apical views, respectively. All studies were digitally stored and analyzed offline by 2 experienced cardiologists who were not involved in the clinical follow-up and were therefore unaware of each patient’s clinical outcome. The AV and VV intervals were optimized by programming the devices following a standardized protocol. The AV interval was analyzed with pulsed Doppler, studying the LV filling flow pattern and trying to separate the A wave from the E wave to obtain the longest LV diastolic filling time. LV diastolic filling time was evaluated at 3 AV intervals: 160, 140, and 120 ms, choosing the interval that yielded the longest LV filling time without interrupting the A wave. Once the optimal AV interval was established, the optimal VV interval was chosen empirically: either right ventricular preactivation (VV ⫽ 30 ms), simultaneous biventricular pacing (VV ⫽ 0 ms), or LV preactivation (VV ⫽ ⫺30 ms). The optimal VV interval was the interval that yielded the best intraventricular synchrony as demonstrated by tissue Doppler imaging, with a greater superposition of the curves of displacement of 2 opposite LV walls (Figure 1). To check that assessment of the best synchrony correlated with the best hemodynamic response,11,16 the velocity–time integral (VTI) at the aortic valve was evaluated with pulsed-wave Doppler in 30 random patients at each of the VV delays tested, and the agreement for determining the best intervals was evaluated. Quantitative variables are expressed as mean ⫾ SD, whereas qualitative variables are expressed as number and percentage. Student’s t test for paired data was used to compare echocardiographic measurements. Discrete variables were compared using the chi-square test. Functional class before and after CRT was compared using Wilcoxon’s sign test. Concordance between aortic VTI and tissue tracking curves for assessing the optimal VV interval was analyzed with the ␬ coefficient. Statistical significance was defined at p ⬍0.05. All data were analyzed using SPSS version 11.0 (SPSS, Inc., Chicago, Illinois). Results One hundred patients who had received CRT devices with or without implantable cardioverter defibrillators were studied (27 [55%] in the nonoptimized group and 36 [70%] in the optimized group received defibrillators). Eighty-one patients (81%) were men, and the mean age was 70 ⫾ 8 years. Among them, 49 patients (49%) had simultaneous biventricular pacing systems, and the remaining 51 (51%) received sequential biventricular pacing devices that were optimized after implantation. At baseline, there were no differences in clinical characteristics, functional status, or LV function between the 2 groups (Table 1). Devices without the capability for VV programming were set at a standard AV interval of 120 ms (sensed AV

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Figure 1. VV interval optimization by assessing intraventricular synchrony with the evaluation of tissue displacement curves of the lateral and septal walls in the 4-chamber (4Ch) apical view and of the anterior and inferior walls in the 2-chamber (2Ch) apical view. The highest level of superposition of the tracings was observed with LV preactivation at ⫺30 ms, which was chosen as the optimal programming. Table 1 Baseline clinical and echocardiographic characteristics (p ⫽ NS) Variable

Age (yrs) 6-min walking test (m) Minnesota Living With Heart Failure Questionnaire score NYHA functional class Ischemic cause QRS (ms) LV end-diastolic volume (ml) LV end-systolic volume (ml) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV ejection fraction (%) LV cardiac output (L/min)

Nonoptimized Group (n ⫽ 49)

Optimized Group (n ⫽ 51)

71 ⫾ 7 307 ⫾ 88 41 ⫾ 20

69 ⫾ 8 336 ⫾ 160 43 ⫾ 21

3.0 ⫾ 0.5 23 (47%) 177 ⫾ 29 226 ⫾ 89 175 ⫾ 78 74 ⫾ 7 61 ⫾ 9 23 ⫾ 6 3.7 ⫾ 0.8

3.0 ⫾ 0.6 24 (47%) 173 ⫾ 23 215 ⫾ 80 161 ⫾ 75 73 ⫾ 10 58 ⫾ 10 25 ⫾ 8 3.8 ⫾ 1.5

NYHA ⫽ New York Heart Association.

delay ⫽ 100 ms) and a VV interval of 0 ms in all 49 patients, with a basic heart rate of 60 beats/min. Device optimization, including optimal AV and VV interval assessment, was performed in all 51 patients who had received devices with sequential biventricular stimulation capability. Among these, AV optimization was not performed in 13 patients (25%) because of the presence of permanent atrial fibrillation. In most patients (n ⫽ 20 [39%]), the optimal AV delay was set at 140 ms; in 12 patients (23%), an AV interval of 120 ms was selected, and in only 6 patients (12%), an AV delay of 160 ms was set because it yielded the best diastolic filling time. LV preactivation at ⫺30 ms was chosen in most patients (n ⫽ 37 [72%]) as the setting that provided the greatest degree of LV synchrony. Simultaneous biventricular pacing (VV delay ⫽ 0 ms) was considered optimal in 11 patients (21%), whereas only 3 patients (6%) benefited more from right ventricular preactivation (VV ⫽ 30 ms). In 30 randomly selected patients, concordance between optimal VV delay by tissue displacement curves and by aortic VTI was good (␬ coefficient ⫽ 0.66, p ⬍0.01). Ninety-eight patients (98%) completed 6-month followup. Two patients were lost to follow-up because they lived

Table 2 Events according to cardiac resynchronization therapy device optimization at 6 month follow-up Variable

Combined end point (nonresponders)* Cardiac death or heart transplantation Improvement ⬍10% in 6-min walking test Distance covered in 6-min walking test (m) ⌬ distance covered in 6-min walking test (m) NYHA functional class Quality-of-life score

Nonoptimized CRT (n ⫽ 47)

Optimized CRT (n ⫽ 51)

p Value

11 (27%)

10 (23%)

NS

3 (6%)

4 (7%)

NS

9 (19%)

5 (15%)

NS

393 ⫾ 123

497 ⫾ 167

⬍0.01

84 ⫾ 128

136 ⫾ 160

NS

2.0 ⫾ 0.7 28 ⫾ 17

2.0 ⫾ 0.6 22 ⫾ 18

NS NS

* Combined end point at 6-month follow-up: cardiovascular death, heart transplantation, or ⬍10% improvement in the 6-minute walking test. Abbreviation as in Table 1.

far away from our referring area. By this time, 1 patient (1%) had been transplanted, 6 (6%) had died, and 14 (14%) had not improved the distance covered in the 6-minute walking test by ⬎10%. Therefore, according to the main combined end point of the study, a total of 21 patients (21%) were nonresponders at 6-month follow-up. Although the optimized group tended to have fewer nonresponders than the nonoptimized group, there was no significant clinical difference in the main clinical end points. Nor were there differences in New York Heart Association functional class or the score obtained on the quality-of-life test at 6-month follow-up. However, patients with optimized devices performed slightly better on the 6-minute walking test. In the optimized patients, the distance walked in the 6-minute test was slightly longer (497 ⫾ 167 m in the optimized patients vs 393 ⫾ 123 m in the nonoptimized patients, p ⬍0.01) and the quality-of-life score lower (22 ⫾ 18 in the optimized patients vs 28 ⫾ 17 in the nonoptimized patients, p ⫽ NS) at 6-month follow-up (Table 2). When we excluded patients with atrial fibrillation as the baseline rhythm (n ⫽ 20, 7 in the nonoptimized group and 13 in the optimized group), we also found a similar impact

Heart Failure/CRT Device Optimization Table 3 Echocardiographic characteristics at six-month follow-up Variable

LV end-diastolic volume (ml) LV end-systolic volume (ml) LV end-diastolic diameter (mm) LV end-systolic diameter (mm) LV ejection fraction (%) ⌬ LV ejection fraction (%) LV cardiac output (L/min)

Nonoptimized CRT (n ⫽ 47)

Optimized CRT (n ⫽ 51)

p Value

204 ⫾ 82 151 ⫾ 71 73 ⫾ 10 54 ⫾ 13 28 ⫾ 9 20 ⫾ 23 3.6 ⫾ 0.5

197 ⫾ 82 140 ⫾ 71 71 ⫾ 10 53 ⫾ 15 30 ⫾ 9 23 ⫾ 45 4.3 ⫾ 1.4

NS NS NS NS NS NS ⬍0.05

of device optimization on clinical outcomes, with only a nonsignificant trend toward fewer events in the optimized group (incidence of the combined end point: 11 [28%] in the nonoptimized group vs 7 [19%] in the optimized group, p ⫽ 0.4). Table 3 lists LV dimensions and function 6 months after device implantation in patients with optimized and nonoptimized devices. The 2 groups showed improved LV systolic function and reduced LV diameters and volumes at follow-up. There was a nonsignificant tendency toward greater remodeling in optimized patients, although LV cardiac output was significantly higher in the optimized group. Discussion Our results show that the optimization of AV and VV intervals in CRT devices slightly increases cardiac output and improves functional performance, as reflected in the distance covered in the 6-minute walking test at 6-month follow-up examination of patients with heart failure and LBBB. However, optimization did not increase the percentage of responders or the extent of LV reverse remodeling. Although CRT provided a significant benefit in the 2 groups, the events observed and the LV reverse remodeling in patients with optimized devices were not significantly better than in the nonoptimized group. With a larger population or a longer follow-up period, differences in LV reverse remodeling or hemodynamics might have become more evident, but the small clinical differences found in our study (on the 6-minute walking test alone or in the quality of life when excluding patients with atrial fibrillation) suggest that the added clinical benefit of CRT optimization is slight and should be counterbalanced by the cost and the time required for optimization in patients with LV dysfunction and LBBB. Our results are in concordance with those of a study by Mortensen et al,12 who compared the response to CRT at 3-month follow-up of optimized patients and patients treated with simultaneous biventricular pacing. They observed that although there was a significant improvement in functional class and 6-minute walking distance with CRT in the 2 groups, there was no significant difference in the benefit obtained. Bordachar et al17 reported an incremental benefit in cardiac performance and LV synchrony in patients who underwent VV optimization. However, that study did not report any clinical follow-up. More recently, Leon et al11 described similar findings at 6-month follow-up in a

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large series of patients from the Multicenter InSync Randomized Clinical Evaluation (MIRACLE) and InSync III studies. Boriani et al16 recently reported no changes in quality of life or functional class after VV optimization. However, none of these studies included hard events (cardiac death or transplantation) at follow-up. As far as we know, there is no more evidence that the optimization of AV and VV intervals provide an incremental clinical benefit at longer term follow-up. Accordingly, we believe that our findings in a consecutive series of patients from a singlecenter experience, despite the limitations inherent in a nonrandomized study, provide more data regarding the clinical utility of optimizing CRT devices. It may be also argued that a 15% to 20% increment in distance walked is a tremendous benefit in the context of patients with heart failure, as reported in the MIRACLE trial.18 Nonetheless, this must be counterbalanced with the personal and time-consuming cost of optimizing the devices. In ⬎70% of our patients, LV preactivation at ⫺30 ms with a relatively short AV interval was chosen as optimal. Previous studies from our group have demonstrated that LV transmural activation time is about 30 ms8; consequently, considering that the LV lead lies on the epicardium, LV preactivation at ⫺30 ms may well be the optimal sequence in this group of patients with LBBB. Other investigators have obtained similar results studying invasively the effect of VV optimization on LV dP/dt.5,7 Conversely, other investigators who have used echocardiographic methods to optimize devices, such as the effect on Doppler-derived LV dP/dt or cardiac output, have reported that up to 25% of patients can benefit more from simultaneous biventricular or right ventricular preactivation.9,19 Differences in the positioning of the right ventricular lead (outflow tract or apex) or in baseline conduction abnormalities of the studied population may account for these discrepancies in optimal VV programming. The fact that several investigators have reported different optimal programming schedules5,7,9,19 is a reflection of the wide variability existing in the underlying conduction abnormalities and LV mechanical asynchrony in patients who undergo CRT. Therefore, individualized programming of the devices is theoretically important to obtain an incremental benefit.20 This may be of great interest in patients with narrow QRS widths, with right bundle branch block, or upgraded to CRT from conventional pacing in whom the conduction abnormalities may be less homogenous than in a population with LBBB such as that included in our study. However, in view of the relative small incremental benefit observed, simple and rapid methods are warranted to select the best programming. In this study, we assessed only a few AV and VV delays. Some patients might have improved more with longer delays, especially those with ischemic cardiomyopathy, who may require longer VV intervals because of the presence of scar tissue resulting in a slower conduction velocity.21 However, the limited data on this issue suggest that the effect of different VV delays on hemodynamics varies within a small range (VV ⫽ ⫹20 to ⫺20 ms). We did not check the programming of the devices at follow-up, which could have improved the outcomes in the optimized group. Additionally, there is no consensus on whether it is better to optimize first the AV or the VV interval; in our patients, we checked

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the AV delay after optimizing the VV interval, and we made no changes in any patient. Finally, the optimal AV and VV intervals were selected on the basis of the greatest intraventricular LV synchrony obtained, because this has been shown to have prognostic implications.22 Although there is no established consensus on what is the most adequate or accurate method to evaluate intraventricular LV synchrony, tissue Doppler imaging– based techniques seem to be the most useful at present.23 In our patients, we used the degree of superposition between the displacement curves of 2 opposite myocardial segments (Figure 1), and we chose the VV interval. We are aware that this method, like others used by different investigators, is not standardized and may therefore have resulted in inadequate optimizations of the devices; as a result, no added clinical benefit would be expected in comparison with simultaneous biventricular pacing. In contrast, the measurement of time to peak velocities or peak strain may be cumbersome in patients with suboptimal quality and noisy traces, and indeed, variability in measurement has been pointed out as a limitation in the use of this method to assess LV asynchrony.23,24 Finally, in our experience, when the VV interval is evaluated with other methodologies, such as surface electrocardiography25 or, as demonstrated in the present study, the aortic VTI, we obtain a good correlation with echocardiography, supporting the validity of this echocardiographic optimization method. 1. Cleland JGF, Daubert J-C, Erdmann E, Freemantle N, Gras D, Kappenberger L, Tavazzi L; Cardiac Resynchronization–Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352:1539 –1549. 2. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, Carson P, Di Carlo L, De Mets D, White BG, et al. Cardiacresynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004;350:2140 –2150. 3. Bradley DJ, Bradley EA, Baughman KL, Berger RD, Calkins H, Goodman SN, Kass DA, Powe NR. Cardiac resynchronization and death from progressive heart failure: a meta-analysis of randomized controlled trials. JAMA 2003;289:730 –740. 4. Diaz-Infante E, Mont L, Leal J, Garcia-Bolao I, Fernandez-Lozano I, Hernandez-Madrid A, Perez-Castellano N, Sitges M, Pavon-Jimenez R, Barba J, et al. Predictors of lack of response to resynchronization therapy. Am J Cardiol 2005;95:1436 –1440. 5. van Gelder BM, Bracke FA, Meijer A, Lakerveld LJ, Pijls NH. Effect of optimizing the VV interval on left ventricular contractility in cardiac resynchronization therapy. Am J Cardiol 2004;93:1500 –1503. 6. Porciani MC, Dondina C, Macioce R, Demarchi G, Pieragnoli P, Musilli N, Colella A, Ricciardi G, Michelucci A, Padeletti L. Echocardiographic examination of atrioventricular and interventricular delay optimization in cardiac resynchronization therapy. Am J Cardiol 2005;95:1108 –1110. 7. Perego GB, Chianca R, Facchini M, Frattola A, Balla E, Zucchi S, Cavaglia S, Vicini I, Negretto M, Osculati G. Simultaneous vs. sequential biventricular pacing in dilated cardiomyopathy: an acute hemodynamic study. Eur J Heart Fail 2003;5:305–313. 8. Berruezo A, Mont L, Nava S, Chueca E, Bartholomay E, Brugada J. Electrocardiographic recognition of the epicardial origin of ventricular tachycardias. Circulation 2004;109:1842–1847. 9. Sogaard P, Egeblad H, Pedersen AK, Kim WY, Kristensen BO, Hansen PS, Mortensen PT. Sequential versus simultaneous biventricular resynchronization for severe heart failure: evaluation by tissue Doppler imaging. Circulation 2002;106:2078 –2084.

10. Kass DA, Chen CH, Curry C, Talbot M, Berger R, Fetics B, Nevo E. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation 1999;99:1567–1573. 11. Leon AR, Abraham WT, Brozena S, Daubert JP, Fisher WG, Gurley JC, Liang CS, Wong G. Cardiac resynchronization with sequential biventricular pacing for the treatment of moderate-to-severe heart failure. J Am Coll Cardiol 2005;46:2298 –2304. 12. Mortensen PT, Sogaard P, Mansour H, Ponsonaille J, Gras D, Lazarus A, Reiser W, Alonso C, Linde CM, Lunati M, et al. Sequential biventricular pacing: evaluation of safety and efficacy. Pacing Clin Electrophysiol 2004;27:339 –345. 13. Schiller NB, Shah PM, Crawford M, DeMaria A, Devereux R, Feigenbaum H, Gutgesell H, Reichek N, Sahn D, Schnittger I, et al. Recommendations for quantitation of the left ventricle by two-dimensional echocardiography. American Society of Echocardiography Committee on Standards, Subcommittee on Quantitation of Two-Dimensional Echocardiograms. J Am Soc Echocardiogr 1989;2:358 –367. 14. St. John Sutton MG, Plappert T, Abraham WT, Smith AL, DeLurgio DB, Leon AR, Loh E, Kocovic DZ, Fisher WG, Ellestad M, et al. Effect of cardiac resynchronization therapy on left ventricular size and function in chronic heart failure. Circulation 2003;107:1985–1990. 15. Pitzalis MV, Iacoviello M, Romito R, Massari F, Rizzon B, Luzzi G, Guida P, Andriani A, Mastropasqua F, Rizzon P. Cardiac resynchronization therapy tailored by echocardiographic evaluation of ventricular asynchrony. J Am Coll Cardiol 2002;40:1615–1622. 16. Boriani G, Muller CP, Seidl KH, Grove R, Vogt J, Danschel W, Schuchert A, Djiane P, Biffi M, Becker T, et al. Randomized comparison of simultaneous biventricular stimulation versus optimized interventricular delay in cardiac resynchronization therapy. The Resynchronization for the Hemodynamic Treatment for Heart Failure Management II Implantable Cardioverter Defibrillator (RHYTHM II ICD) study. Am Heart J 2006;151:1050 –1058. 17. Bordachar P, Lafitte S, Reuter S, Sanders P, Jais P, Haissaguerre M, Roudaut R, Garrigue S, Clementy J. Echocardiographic parameters of ventricular dyssynchrony validation in patients with heart failure using sequential biventricular pacing. J Am Coll Cardiol 2004;44:2157– 2165. 18. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, Kocovic DZ, Packer M, Clavell AL, Hayes DL, et al. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002;346:1845– 1853. 19. Leon AR, Liang CS, Abraham WT, Chinchoy E, Hill MRS; US InSync III Investigators and Coordinators. Interventricular delay increases stroke volume in cardiac resynchronization patients. Eur Heart J 2002;23(suppl):529. 20. Fung JW, Yu CM, Yip G, Zhang Y, Chan H, Kum CC, Sanderson JE. Variable left ventricular activation pattern in patients with heart failure and left bundle branch block. Heart 2004;90:17–19. 21. Rodriguez LM, Timmermans C, Nabar A, Beatty G, Wellens HJ. Variable patterns of septal activation in patients with left bundle branch block and heart failure. J Cardiovasc Electrophysiol 2003;14: 135–141. 22. Bader H, Garrigue S, Lafitte S, Reuter S, Jais P, Haissaguerre M, Bonnet J, Clementy J, Roudaut R. Intra-left ventricular electromechanical asynchrony. A new independent predictor of severe cardiac events in heart failure patients. J Am Coll Cardiol 2004;43:248 –256. 23. Bax JJ, Ansalone G, Breithardt OA, Derumeaux G, Leclercq C, Schalij MJ, Sogaard P, St. John Sutton M, Nihoyannopoulos P. Echocardiographic evaluation of cardiac resynchronization therapy: ready for routine clinical use? A critical appraisal. J Am Coll Cardiol 2004; 44:1–9. 24. Yu CM, Fung JW, Zhang Q, Chan CK, Chan YS, Lin H, Kum LC, Kong SL, Zhang Y, Sanderson JE. Tissue Doppler imaging is superior to strain rate imaging and postsystolic shortening on the prediction of reverse remodeling in both ischemic and nonischemic heart failure after cardiac resynchronization therapy. Circulation 2004;110:66 –73. 25. Vidal B, Tamborero D, Mont L, Sitges M, Delgado V, Berruezo A, Diaz Infante E, Tolosana JM, Pare C, Brugada J. Electrocardiographic optimization of interventricular delay in cardiac resynchronization therapy: correlation with echocardiography. J Cardiovasc Electrophysiol, in press.