Interventricular Delay Interval Optimization in Cardiac Resynchronization Therapy Guided by Echocardiography Versus Guided by Electrocardiographic QRS Interval Width

Interventricular Delay Interval Optimization in Cardiac Resynchronization Therapy Guided by Echocardiography Versus Guided by Electrocardiographic QRS Interval Width Matteo Bertini, MD*, Matteo Ziacchi, MD, Mauro Biffi, MD, Cristian Martignani, MD, PhD, Davide Saporito, MD, Cinzia Valzania, MD, Igor Diemberger, MD, Elena Cervi, MD, Jessica Frisoni, BS, Diego Sangiorgi, BS, Angelo Branzi, MD, and Giuseppe Boriani, MD, PhD Present devices for cardiac resynchronization therapy offer the possibility of tailoring the hemodynamic effect of biventricular pacing by optimization of the interventricular delay (VV) beyond atrioventricular (AV)-interval optimization. It was not yet defined whether a QRS width– based strategy may be a helpful tool for echocardiography for device programming. The aim of the study was to investigate the relation between VV-interval optimization guided by echocardiography and guided by QRS interval width. One hundred six patients with a cardiac resynchronization therapy device for >3 months were enrolled. All patients underwent echocardiographic AV and VV delay optimization. The AV interval was optimized according to the E wave-A wave (EA) interval and left ventricular filling time. At the optimal AV delay, VV optimization was performed by measuring the aortic velocity time integral at 5 different settings: simultaneous right and left ventricle output, left ventricle pre-excitation (left ventricle ⴙ 40 and 80 ms, respectively), and right ventricle preexcitation (right ventricle ⴙ 40 and 80 ms, respectively). A 12-lead electrocardiogram was recorded and QRS duration was measured in the lead with the greatest QRS width. The electrocardiographic (ECG)-optimized VV interval was defined according to the narrowest achievable QRS interval among 5 VV intervals. The echocardiographic-optimized VV interval was left ventricle ⴙ 40 ms in 28 patients, left ventricle ⴙ 80 ms in 15 patients, simultaneous in 46 patients, right ventricle ⴙ 40 ms in 14 patients, and right ventricle ⴙ 80 ms in 3 patients. Significant concordance (␬ ⴝ 0.69, p <0.001) was found between the echocardiographic- and ECG-optimized VV interval. In conclusion, significant concordance appeared to exist during biventricular pacing between VV programming based on the shortest QRS interval at 12-lead ECG pacing and echocardiographic-guided VVinterval optimization. A combined ECG- and echocardiographic approach could be a less time-consuming solution in performing this operation. © 2008 Elsevier Inc. All rights reserved. (Am J Cardiol 2008;102:1373–1377) Cardiac resynchronization therapy (CRT) can improve cardiac function and clinical status in patients with severe heart failure, and a wide QRS has traditionally been used as a marker of patients with mechanical dyssynchrony.1–5 Although relatively good correlation between interventricular dyssynchrony and QRS duration has been reported, no significant correlation existed between intraventricular dyssynchrony and QRS width.6,7 Present devices for CRT offer the possibility of tailoring the hemodynamic effect of biventricular pacing by optimization of the interventricular (VV) interval, beyond atrioventricular (AV) delay optimization. At present, there is no gold-standard technique for VVinterval optimization, and in previous reports, its usefulness was controversial.8 –10 This procedure was also time consuming and needed considerable expertise and therefore Institute of Cardiology, University of Bologna, Bologna, Italy. Manuscript received May 5, 2008; revised manuscript received and accepted July 13, 2008. *Corresponding author: Tel: ⫹39-05-1636-3531; Fax: ⫹39-05-1344859. E-mail address: [email protected] (M. Bertini). 0002-9149/08/$ – see front matter © 2008 Elsevier Inc. All rights reserved. doi:10.1016/j.amjcard.2008.07.015

was often not performed. This study examined the relation between VV-interval optimization guided using echocardiography or QRS interval width. Methods One hundred six patients with a CRT device for ⱖ3 months were enrolled. All patients underwent echocardiographic optimization of AV and VV delay. Echocardiographic images were assessed using a Philips Sonos 5500 Ultrasound System (Philips Ultrasound, Andover, Massachusetts) equipped with a harmonic fusion imaging probe (s3) and off-line cine loop analysis software. AV delays were analyzed from 60 to 200 ms, with steps of 10 ms. Transmitral flow was analyzed using pulsed Doppler to find the AV delay that provided the longest left ventricular filling time and EA interval without interruption of the A wave.11 When the AV delay with the best hemodynamic effect was found, VV-interval optimization was performed measuring the aortic velocity time integral as a surrogate of stroke volume at the 5 different settings of simultaneous right and left ventricle output, left ventricle pre-excitation www.AJConline.org

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The American Journal of Cardiology (www.AJConline.org) Table 1 Population baseline characteristics Age (yrs) Men (%) Cause (%) Ischemic Nonischemic New York Heart Association class (%) I–II III–IV ␤ Blockers (%) QRS width (ms) Left ventricular EF (%) Left ventricular end-diastolic volume (ml) Left ventricular end-systolic volume (ml)

65 ⫾ 12 78% 34% 66% 71 (67%) 35 (33%) 87% 164 ⫾ 25 30 ⫾ 9 201 ⫾ 75 143 ⫾ 62

Population included patients with a CRT device for ⱖ3 months (n ⫽ 106). Values expressed as mean ⫾ SD, percent, or number (percent).

Figure 1. Example of determination of ECG-optimized VV interval shows QRS complex in D1 and V1 for each of 5 VV intervals. In this example, D1 and V1 show a similar QRS width and could be suitable for identification of the ECG-optimized VV interval. Of these 5 QRS measurements, the value corresponding to the narrowest QRS was considered the ECGoptimized VV interval. In this case, the ECG-optimized VV interval was simultaneous (left [LV] and right ventricle [RV] VV interval ⫽ 0 ms).

(left ventricle ⫹ 40 and 80 ms, respectively), and right ventricle pre-excitation (right ventricle ⫹ 40 and 80 ms, respectively). The echocardiographic-optimized VV interval was determined by maximizing the aortic velocity time integral (as previous described).12 Echocardiographic data were averaged from values independently collected by 2 experienced investigators during the same examination, both blinded to all programming information. Interobserver variability, calculated according to the formula |observer 1 ⫺ observer 2|/[(observer 1 ⫹ observer 2/2] · 100%, was 2.3% for AV-interval optimization and 6.3% for VV-interval optimization. At each tested VV interval, a 12-lead electrocardiogram was recorded at a paper speed of 25 mm/s and a 10-mm/mV gain, and QRS duration was measured in the lead with the greatest QRS width from the first deflection of the QRS complex to its terminal isoelectric component (mean of 3 measurements of 3 consecutive cycles performed by 2 independent operators). According to published reports, the greatest QRS width was deemed to reflect interventricular mechanical dyssynchrony.6,7 Interobserver variability, calculated as described, was ⬍5%. QRS duration was assessed manually using a graduated measuring instrument with accuracy of 0.25 mm (10 ms) in the lead with the widest QRS width at the 5 VV offsets. The electrocardiographic (ECG)optimized VV interval was defined as that corresponding to the narrowest QRS in these 5 measurements (Figure 1). The ECG-optimized VV interval was therefore deemed to be related to the least interventricular dyssynchrony. Patients could be responders or nonresponders to CRT on either an objective or purely clinical evaluation. On an objective evaluation, we defined a patient who did not show improvement in left ventricular ejection fraction (EF) and/or end-systolic volume as a nonresponder. On echocardio-

Table 2 Results of echocardiographic-optimized interventricular (VV) interval Ventricle Stimulated First Left ventricle VV ⫹ 40 ms VV ⫹ 80 ms Right ventricle VV ⫹ 40 ms VV ⫹ 80 ms Simultaneous (VV ⫽ 0 ms)

No. of Patients 43 (41%) 28 (27%) 15 (14%) 17 (16%) 14 (13%) 3 (3%) 46 (43%)

graphic examination after ⱖ3 months of CRT, our criteria for assessing echocardiographic response were increased EF ⱖ5% (absolute value) and/or decreased left ventricular endsystolic volume (ⱖ15% compared with baseline), as in published reports.13 An improvement of ⱖ1 New York Heart Association class was used to define clinical responders.13 Descriptive analysis was performed for all relevant continuous variables. Weighted ␬ statistic was used to evaluate agreement between the echocardiographic-optimized VV interval versus the ECG-optimized VV interval. Results were classified as ␬ ⬍0.00, poor; ␬ ⫽ 0.00 to 0.20, slight; ␬ ⫽ 0.21 to 0.40, fair; ␬ ⫽ 0.41 to 0.60, moderate; ␬ ⫽ 0.61 to 0.80, substantial; and ␬ ⫽ 0.81 to 1.00, almost perfect agreement.14 Ratings were weighted by 1.000, 0.8000, and 0.0000. A Bland-Altman graph was also used to evaluate concordance between QRS width at echocardiographic and ECG optimization. The 95% exact confidence interval corresponded to the 2.5% and 97.5% percentiles of the listed total number of possible permutations. Percentiles and median QRS widths at different VV intervals were represented in a box plot graph. Results General characteristic of the study population (106 patients with a CRT device for ⱖ3 months) were listed in Table 1. At implantation, 95 were New York Heart Association class III, whereas 11 were New York Heart Association class IV. At follow-up, 79 of 106 (75%) had improved by ⱖ1 New York Heart Association class (71 New York Heart Associ-

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Table 3 The ␬ statistic for electrocardiographic (ECG)- versus echocardiographic-optimized interventricular (VV) interval Echocardiographic-optimized VV interval ECG-optimized VV interval Left ventricle stimulated first VV ⫹ 80 ms VV ⫹ 40 ms Simultaneous VV ⫽ 0 ms Right ventricle stimulated first VV ⫹ 40 ms VV ⫹ 80 ms Total

Left Ventricle Stimulated First

Simultaneous

Right Ventricle Stimulated First

Total

VV ⫹ 80 ms

VV ⫹ 40 ms

VV ⫽ 0 ms

VV ⫹ 40 ms

VV ⫹ 80 ms

12 1

0 24

2 2

0 3

0 0

14 30

2

1

35

0

0

38

0 0 15

3 0 28

3 1 43

13 1 17

0 3 3

19 5 106

Weighted ␬ ⫽ 0.69, SE ⫽ 0.08, p ⬍0.001.

Figure 2. QRS width at each tested VV interval, as well as at echocardiographic- and ECG-optimized CRT. The median value of QRS width between echocardiographic- and ECG-optimized CRT is the same. Of the 5 different VV intervals, the most similar median value is for left ventricle (LV)-right ventricle (RV) ⫽ 0 ms (simultaneous), which proved to be the most frequent setting after optimization (Table 2).

ation class I to II, 34 New York Heart Association class III, and 1 New York Heart Association class IV), being responders on a clinical basis. Based on an objective measurement of left ventricular EF and left ventricular endsystolic volume using echocardiography, 73 of 106 (69%) were responders. The echocardiographic-optimized VV interval occurred at different levels of VV-interval setting (Table 2). The ECG-optimized VV interval (as specified) occurred at left ventricle pre-excitation of 80 ms in 14 patients, left ventricle pre-excitation of 40 ms in 30 patients, simultaneous left and right ventricle activation (VV interval ⫽ 0 ms) in 38 patients, right ventricle pre-excitation of 40 ms in 19 patients, and right ventricle pre-excitation of 80 ms in 5 patients. Substantial concordance (weighted ␬ ⫽ 0.69, p ⬍0.0001; ratings weighted by 1.000, 0.8000, and 0.0000; Table 3) was found between the echocardiographic-optimized VV interval and the ECG-optimized VV interval (the latter was the VV interval corresponding to the narrowest QRS of all tested VV intervals, measured in the lead with the widest intrinsic QRS complex).

Figure 3. Bland-Altman plot graph shows significant concordance of QRS width during echocardiographic-optimized VV interval and ECG-optimized VV interval.

Similar concordance was found between the echocardiographic-optimized VV interval and ECG-optimized VV interval in echocardiographic responders (weighted ␬ ⫽ 0.71, p ⬍0.001) and nonresponders (weighted ␬ ⫽ 0.67, p ⬍0.001). Concordance of the echocardiographic- and ECG-optimized VV interval was observed irrespective of patients’ echocardiographic response to CRT (response or no response) assessed using the 3-month echocardiographicevaluation. Percentiles and median values of QRS widths at different VV intervals were represented in a box-plot graph (Figure 2). The Bland-Altman graph emphasized the significant concordance of 2 different methods used to optimize the VV interval in CRT devices (Figure 3). In this study, tailoring of the VV interval occurred at a higher aortic velocity time integral compared with simultaneous biventricular stimulation in 57% of patients.9 Discussion The present study showed substantial agreement between these 2 methods to optimize the VV interval of CRT devices. Tailoring CRT by programming the optimal AV and

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VV intervals is fundamental to ensure proper filling and maximal output of the failing left ventricle at the lowest energy cost.15 Historically, it was shown that AV delay optimization substantially increased cardiac output by ensuring adequate left ventricle filling.16 It thus became common practice to program AV delay based as guided by echocardiography in earlier CRT experience. However, evidence was still needed about the beneficial effect of periodic AV delay optimization during long-term follow up.17,18 The recent generation of CRT devices allowed optimization of the VV interval because of the availability of interventricular offset. In daily practice, echocardiographic assessment of cardiac output using the left ventricular outflow (velocity time integral) at different VV intervals may be the preferred approach to assess optimal VV settings. Adjustment of interventricular pacing intervals further improved cardiac performance compared with simultaneous biventricular pacing in a relevant subgroup of patients.8 This feature can be helpful in achieving a favorable clinical response to CRT in individual patients. Because of the important hemodynamic consequences of VV-interval optimization and the observed high rate of nonresponders reported,19,20 tailoring the interventricular interval in every patient referred for CRT may be of paramount clinical importance. Up to 45% of patients are nonresponders to CRT, assessed using objective measurements of left ventricular function.20 Accordingly, delivery of CRT therapy should be reassessed during follow-up because loading left ventricle conditions change over time because of left ventricular remodeling.17,18 Periodic tailoring of CRT devices is important to maintain the best hemodynamic effect during the long term and enhance benefit from CRT. We previously found that the optimal VV delay may change during follow-up in 41% to 57% of patients. Hence, periodic reassessment may be needed to maintain the clinical benefit.17,18 The main obstacle to systematic optimization and periodic reassessment of AV and VV intervals was the time spent on performing such an evaluation and its dependence on a reliable thoracic window and experienced personnel. It was conceivable that an alternative method could be sought, which proved reliable, non– operator dependent, inexpensive, and suitable to become a built-in feature of a CRT device. The first step would be finding a reliable relation with echocardiographic-based optimization, which was considered the present gold standard. We tested the hypothesis that QRS width, a global marker of cardiac synchronicity, could reflect the outcome of CRT in a broad perspective. As far as global dyssynchrony was concerned, it appeared from our data that the lead with the widest QRS on a surface electrocardiogram provided a reliable target for CRT optimization. Although the ability to identify intraventricular dyssynchrony may be weak at baseline, measurement of QRS width is an inexpensive tool for CRT tailoring. Although baseline QRS duration may fail to predict response to CRT, changes in QRS duration after CRT differed significantly between responders and nonresponders in a number of studies.21–24 In a recent study, QRS delta (baseline QRS duration ⫺ paced QRS during CRT) was an independent predictor of response to CRT after multivariate analysis adjustment. This relation between QRS narrowing and clinical efficacy suggested that after left ventricular lead

placement at the best suitable site has been achieved, the right ventricular lead should be placed to obtain the greatest QRS shortening to improve resynchronization.24 Biventricular pacing reduced QRS duration, whereas left ventricular pacing alone did not, although both could correct intraventricular dyssynchrony. Accordingly, biventricular pacing was associated with a greater decrease in left ventricular volume than left ventricular pacing alone.25 In keeping with these observations, Ghio et al6 showed that interventricular dyssynchrony, more than intraventricular dyssynchrony, was significantly related to QRS duration. Rouleau et al3 showed that QRS duration was a valuable marker of interventricular electromechanical delay and precisely reflected the delayed left ventricular activation. It is thus conceivable that shortened QRS duration is a global measurement of improved myocardial performance and may be used as a marker of improvement during CRT. Use of a leadless electrogram that covers the largest amount of myocardium to mimic a surface electrocardiogram could be a built-in surrogate to allow periodic monitoring of optimized VV programming to maximize the response to CRT. Should prospective studies confirm this approach, an automatic algorithm for continuous CRT monitoring could be developed. For this purpose, the intracardiac source with the widest electrogram (right ventricle coil-to-can, right ventricle ring-to-can) could be suitable. The practical interest of our study was the possibility of using a combined approach for VV interval optimization. Using ECG recording at 5 VV intervals in 40-ms steps as in our observation, the interval with the greatest QRS shortening could be identified and scanned in depth (10-ms steps) to find the optimal VV interval for the patient. Such an approach would greatly decrease the time required for CRT tailoring. In the perspective of a built-in feature, scanning the VV-interval range could be automatically device-operated by the use of an intracardiac electrocardiogram and used to guide VV tuning using echocardiography. The main limitation of this study was the relatively small number of VV intervals tested to optimize the device. We chose only 5 VV intervals at 40-ms distance from each other because we tested every interval with the corresponding surface electrocardiogram, and in particular, we measured QRS width. To obtain differences that we could easily measure, we chose a large difference between VV intervals, otherwise we would have obtained such small differences (⬍10 ms) in QRS width that were less than the accuracy of our instrument to measure QRS width. The principal aim of our study was not to find an alternative method to echocardiography, but to seek a less time-consuming approach to CRT tailoring. After ECG recording, the clinician could perform VV optimization by carefully testing no more than 2 to 3 VV intervals. Ventricular dyssynchrony was not measured using tissue Doppler imaging or speckle tracking analysis because these technologies are not widely available in outpatient clinics and require sophisticated echocardiographic equipment and high expertise. We chose to use simple technology generally available in clinical practice to provide practical hints. 1. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, Garrigue S, Kappenberger L, Haywood GA, Santini M, Bailleul C,

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