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Ann Thorac Surg 2004;78:1678-1683
© 2004 The Society of Thoracic Surgeons

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Original article: cardiovascular

Ventricular Resynchronization by Multisite Pacing Improves Myocardial Performance in the Postoperative Single-Ventricle Patient

^a Cardiothoracic Surgery, Congenital and Pediatric Cardiac Surgery, The University of Chicago Hospitals, Chicago, Illinois, USA
^b Section of Pediatric Cardiology, The University of Chicago Hospitals, Chicago, Illinois, USA
^c Section of Cardiology, The University of Chicago Hospitals, Chicago, Illinois, USA

Accepted for publication April 20, 2004.

^* Address reprint requests to Dr Bacha, Congenital and Pediatric Cardiac Surgery, MC 5040, 5841 S Maryland Ave, University of Chicago Children's Hospital, Chicago, IL, USA 60637
ebacha{at}surgery.bsd.uchicago.edu

Presented at the Fortieth Annual Meeting of The Society of Thoracic Surgeons, San Antonio, TX, Jan 26–28, 2004.

	Abstract

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 
BACKGROUND: Ventricular resynchronization with multisite pacing in heart failure patients results in acute improvement of myocardial performance, but the mechanism is unknown. Our goals were to determine whether multisite pacing results in acute improvement of myocardial performance in postoperative single-ventricle patients, and to elucidate the mechanism by assessing the synchronization of regional ventricular contraction during multisite pacing using real-time three-dimensional echocardiographic imaging.

METHODS: Multisite pacing studies were performed in 26 single-ventricle patients (mean age, 28 months; range, 7 days to 11 years) undergoing some form of single-ventricle palliation (stage I Norwood, 4; aortopulmonary shunt, 1; cavopulmonary shunt, 9; Fontan, 8; Fontan revision, 3; valve replacement, 1). Electrocardiogram, blood pressure, mixed-venous oxygen saturation, and three-dimensional echocardiograms (n = 10) were recorded at baseline and during multisite pacing. Data were analyzed to obtain regional volume-time curves for 16 three-dimensional segments of the systemic ventricle. An index of asynchrony was calculated at baseline and during pacing as the standard deviation of all segmental volume-time curves from onset to end of ejection.

RESULTS: With multisite pacing performed at a median postoperative day 2 (range, 0 to 9), QRS duration decreased in 24 of 26 patients (93.9 ± 17.5 versus 71.7 ± 10.8 ms; p < 0.001); systolic blood pressure increased in 25 of 26 patients (86.3 ± 20.0 versus 93.8 ± 20.2 mm Hg; p < 0.001); cardiac index increased in 21 of 22 patients (3.2 ± 0.8 versus 3.7 ± 1.0 L · min^–1 · m^–2; p < 0.001); and the index of asynchrony improved in 8 of 10 patients (10.3 ± 4.8 versus 6.0 ± 1.4; p < 0.04).

CONCLUSIONS: Multisite pacing improves cardiac performance after single-ventricle palliation. Real-time three-dimensional echocardiography demonstrated that multisite pacing improved the synchrony of ventricular contraction.

	Introduction

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 
Cardiac resynchronization therapy (CRT) with multisite pacing is effective for treatment of heart failure associated with left ventricular dyssynchrony in adults [1]. Ventricular dyssynchrony from intraventricular or interventricular conduction delay results in reduced regional and global ejection fraction [2]. By pacing the right and left ventricles simultaneously, CRT attempts to achieve a more rapid and uniform ventricular depolarization, resulting in a more synchronous contraction pattern [3].

Acute studies in patients with congenital heart disease and right bundle-branch block have shown that single-site right ventricular (RV) pacing or biventricular pacing results in increased arterial blood pressure, cardiac index, and maximum rate of increase of RV pressure [4, 5]. The optimal site of pacing was inconsistent and found to vary among patients. We have thus taken the approach of multisite ventricular stimulation with empiric and consistent placement of epicardial pacing leads in postoperative congenital heart disease patients with one-ventricle and two-ventricle physiology and have shown acute increases in arterial blood pressure and cardiac output with multisite pacing [6]. Unlike reparative surgery in two-ventricle patients in whom issues surrounding myocardial protection have been well worked out, the single-ventricle (SV) patient undergoing palliative surgery remains at risk for postoperative myocardial dysfunction [7, 8]. In fact, myocardial dysfunction remains the leading cause of death after stage I Norwood palliation [8, 9] and after the Fontan operation [7].

Real-time, three-dimensional (3D) echocardiography is an emerging technology that allows for acquisition of full-volume 3D echocardiographic data from a single acoustic window [10]. The data can then be transferred to an off-line computer and used to generate ventricular volumes and regional and global ejection fractions. The change in volume with time can be quantified for individual ventricular segments and used to create regional volume-time curves for an entire cardiac cycle. Synchronization of contraction of individual ventricular segments can then be assessed.

The aims of this study were to (1) assess the acute hemodynamic changes in patients with SV physiology with multisite pacing, and (2) assess whether the resynchronization of regional ventricular contraction seen during multisite pacing in two-ventricle patients is also seen with SV patients.

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 
Patient Population
Patients undergoing SV palliation at the University of Chicago Children's Hospital were evaluated for participation in the study. Inclusion criterion consisted of all SV patients undergoing palliative surgery requiring cardiopulmonary bypass, irrespective of their electrocardiographic morphology. Patients were excluded if they required extracorporeal membrane oxygenation in the postoperative period. The institutional review board approved the study protocol, and all patients or parents of minors gave written consent.

Pacing Study
Acute pacing studies were performed at the bedside in the pediatric intensive care unit after surgery. At the time of surgery, two atrial and three ventricular unipolar temporary epicardial pacing leads were placed. The ventricular leads were placed on the outflow tract near the semilunar valve, on the right side of the anterior wall (near the atrioventricular [AV] groove), and on the ventricular apex in all patients, as previously described [6]. Pacing was performed using Medtronic dual-chamber temporary pacemakers (Medtronic, Minneapolis, MN). The atrial leads were placed in the positive and negative ports of the atrial connector. For multisite pacing, the outflow and right lateral or anterior wall ventricular leads were placed in the negative port and the apex lead was placed in the positive port of the ventricular connector. This allowed for simultaneous ventricular stimulation from two sites (outflow and lateral or anterior wall). For single-site pacing, the outflow or lateral or anterior wall lead was placed in the negative port as the single stimulation site. Pacing was performed in the DDD (dual-chamber) mode with atrial sensing of intrinsic sinus rhythm. The AV delay was adjusted to achieve ventricular pacing with the narrowest QRS duration as assessed by continuous electrocardiogram recording. Baseline mixed venous oxygen saturation, blood pressure, and continuous electrocardiogram were obtained and then repeated after 20 minutes of pacing. Multisite pacing was performed in all patients. After a period of 5 to 10 minutes off pacing, additional ventricular pacing was performed from a single ventricular site. The AV interval was the same with single-site and multisite pacing. Hemodynamics were reassessed during single-site pacing from both the outflow and anterior or lateral wall and used for comparison with multisite pacing.

Echocardiographic Study
Full-volume, real-time 3D echocardiographic studies were performed using a special matrix array transducer (4x; Phillips, Andover MA) connected to an ultrasound machine equipped with dedicated software (Sonos 7500; Phillips) [10]. A pyramid of echocardiographic data (85 x 90 degrees) encompassing the ventricle was obtained from the apical four-chamber position for more than four cardiac cycles gated to the R wave of the electrocardiogram. The data were transferred to an off-line computer and further analyzed using special software (CardioView RT; TomTec, Unterschleibheim, Germany). After manual definition of the AV valve and interventricular septum (defined as the wall separating the systemic ventricle from the diminutive ventricle), six to eight long-axis two-dimensional planes of the ventricle were automatically created and analyzed. Semiautomated border detection was used to trace the endocardial border for 5 to 15 frames per cardiac cycle. A ventricular cast was then automatically constructed, from which end-systolic volume, end-diastolic volume, and global ejection fraction (calculated as end-diastolic volume minus end-systolic volume divided by end-diastolic volume times 100) could be computed. The ventricle was then divided into 16 segments from apex to base, and a graph of the change in volume with time for an entire cardiac cycle was constructed for each region (see Fig 1 for example). Regional volume curves were then analyzed for each of the 16 ventricular segments. The time from end of diastole (maximal volume) to end of ejection (minimal volume) for each region (end ejection time [EET]) was determined, and the mean value for the combined segments was calculated (mean EET). We defined an index of asynchrony as the standard deviation of the mean time from end diastole to end ejection (standard deviation of mean EET). We then determined the difference between the time to end ejection for an individual region and the mean for all regions (individual EET minus mean EET). This value was used to compare the degree of asynchrony of each region in the baseline state and during pacing.

View larger version (30K): [in this window] [in a new window]   Fig 1. Regional volume curves (change in volume [regional endocardial displacement in three dimensions] with time for an entire cardiac cycle) obtained from 16 ventricular segments (from apex to base) in a 6-month-old patient with unbalanced atrioventricular canal and bidirectional Glenn shunt; multisite pacing study on postoperative day 4. (Left panel) Baseline. (Right panel) With pacing.

Statistical Analysis
All data analyzed during multisite pacing was compared with baseline data for each patient. Values are expressed as mean ± standard deviation. Continuous variables were compared using paired Student's t tests. The single-site pacing that resulted in the largest change in cardiac index was compared with multisite pacing using paired Student's t tests. Linear regression analysis was used to compare the change in cardiac index with asynchrony index. A p value of less than or equal to 0.05 was used to assess statistical significance.

	Results

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 
Study Population
The baseline characteristics of the patients are shown in Table 1. Twenty-six patients with SV physiology with a median age of 28 months (range, 7 days to 11 years) were included in the study. Operative procedures included stage I Norwood in 4, modified Blalock-Taussig shunt in 1, bidirectional Glenn shunt in 9, Fontan in 8, Fontan revision in 3, and semilunar valve replacement in 1. The pacing studies were performed on median postoperative day 2 (range, 0 to 9 days). Eight of these patients underwent additional single-site pacing studies to compare with multisite pacing. The median age of these patients was 20 months (range, 5 months to 8 years).

View larger version (28K): [in this window] [in a new window]   Fig 2. Change in QRS duration at baseline and after multisite pacing. Data depicted as mean ± standard deviation.

View larger version (29K): [in this window] [in a new window]   Fig 3. Change in systolic blood pressure (SBP) at baseline and after multisite pacing. Data depicted as mean ± standard deviation.

View larger version (26K): [in this window] [in a new window]   Fig 4. Change in cardiac index (CI) at baseline and after multisite pacing. Data depicted as mean ± standard deviation.

SYNCHRONY OF VENTRICULAR CONTRACTION (ASYNCHRONY INDEX)
Multisite pacing resulted in improved synchrony of segmental ventricular wall systolic motion as assessed by 3D echocardiography. The index of asynchrony decreased in 8 of 10 patients studied (Fig 5). The mean baseline index of asynchrony for all patients was 10.3 ± 4.8 and decreased to 6.0 ± 1.4 with multisite pacing (p < 0.04).

View larger version (28K): [in this window] [in a new window]   Fig 5. Asynchrony index as assessed by real-time three-dimensional echocardiography at baseline and after multisite pacing. Data depicted as mean ± standard deviation.

	Comment

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

Previous studies have shown that patients with right bundle-branch block and congenital heart disease benefit acutely from RV resynchronization therapy [4–6]. Acute epicardial pacing from the RV outflow, RV lateral wall, or left ventricular lateral wall alone or in various combinations resulted in increased blood pressure in patients after surgery for congenital heart disease [4]. This is the first study to focus on SV patients, the most vulnerable among congenital heart disease patients. There is growing support for the hypothesis that the pathophysiology of the failing heart involves to a large degree adverse mechanical energetics, resulting in a reduced ratio between work performed and oxygen consumed [3, 11, 12]. The traditional management of a failing SV after surgery is inotropic support. Most inotropic agents come at the cost of significant side effects such as myocardial energy store depletion and increasing myocardial oxygen consumption. A recent human study comparing dobutamine infusion with CRT showed that CRT enhanced systolic function while modestly lowering myocardial energy demand [11]. The improved efficiency from CRT is not because of improved intrinsic myocyte function. This study suggests that the main advantages of CRT is by synchronizing the timing of different wall segments, thereby achieving a more effective ejection [3, 11]. Two of 10 patients did not have improved synchronization with multisite pacing. However, both patients had a low asynchrony index at baseline and thus may not have had the potential to improve much further.

In most recent studies, the optimal site for pacing varied among patients but correlated with the site that produced the narrowest QRS duration [5, 13]. In an attempt to account for this variability among patients, we have taken the approach of empirically standardizing the intraoperative epicardial lead placements to produce an equidistant triangle with as distant as possible corners. This theoretically would assure as simultaneous stimulation as possible for all ventricular wall segments. These sites are usually readily accessible during surgery for congenital heart disease, and additional testing to determine optimal pacing sites was not done. In the present study, multisite pacing resulted in a significantly greater increase in cardiac index compared with the optimal single-site pacing. Single-site pacing did not result in significant hemodynamic improvement as compared with baseline (no pacing). This implies that there is an additional beneficial effect of resynchronization with multisite pacing likely caused by more effective reestablishment of synchronized ventricular contraction compared with single-site pacing.

Despite the fact that conduction delays in the form of increased QRS duration are relatively rare in SV patients [14], most patients in our study experienced a narrowing of their QRS along with improved hemodynamics. This is consistent with the most recent findings that adult patients with narrow QRS complexes also benefit from CRT [15].

Real-time 3D echocardiography proved to be an ideal modality for assessment of synchrony of regional ventricular contractility. Apical four-chamber images required for 3D analysis were relatively easy to obtain and evaluate in this postoperative study group in which traditional transthoracic echocardiographic images are often limited. Prospective studies are needed to determine whether the baseline or change in the index of asynchrony can be used to predict the response to CRT.

Limitations to this study included dependence on accurate and consistent determination of endocardial border detection for echocardiographic analysis. Variability in this determination was limited by having a single, experienced technician obtain and analyze all 3D echocardiographic images. Multisite and single-site pacing was performed without AV interval optimization during this study. Although AV optimization has been shown to be beneficial in some adults with biventricular pacing, the role in RV or SV resynchronization in younger patients with congenital heart disease is unclear. Single-site pacing in this study was limited to the systemic outflow and lateral wall sites that have been previously shown to result in optimal ventricular resynchronization in two-ventricle patients. More detailed mapping of the ventricle for an optimal single pacing site might have resulted in similar changes in cardiac index compared with multisite pacing. Lastly, the cardiac index at baseline was close to normal at 3.2 L · min^–1 · m^–2. Whether CRT results in a clinically significant improvement in patients with profound myocardial dysfunction after SV palliation remains to be determined.

Future studies will have to prospectively randomize patients to determine whether CRT results in improved myocardial function and survival after surgery for congenital heart disease.

In conclusion, multisite pacing improved cardiac performance after SV palliation. Real-time 3D echocardiography suggests that the mechanism may be caused by improved synchrony of ventricular contraction.

	DISCUSSION

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 
DR HENRY M. SPOTNITZ (New York, NY): Doctor Guyton, Dr Murray, ladies and gentlemen. This is the second excellent study from Dr Bacha's group of multisite pacing after surgery for congenital heart disease. Smaller series by others suggest benefits of biventricular pacing after surgery for acquired heart disease. Our initial operating room studies at New York Presbyterian Hospital in adults with postoperative heart block demonstrate a 10% increase in cardiac index when simultaneous biventricular pacing is compared with single-site left ventricular or right ventricular pacing.

In our research laboratory we find that optimum pacing algorithms in animals with heart block are specific to the form of acute heart failure studied and importantly affected by the interval between right and left ventricular stimulation, right-left delay, or RLD. David Rabkin, Lauren Curtis, and others defined dependence of cardiac output on RLD in critical pulmonary stenosis. In 16 animals, cardiac output with the right preceding the left by 50 ms was 10% to 13% higher than simultaneous right ventricular and left ventricular pacing or maximally delayed right ventricular stimulation. As shown in the small panel, a change of only 20 ms from the optimum RLD could reduce cardiac output 10%.

In an unpublished substudy of INSYNC III in chronic heart failure, David Delurgio of Emory found that RLD optimization more than doubled the stroke volume benefit of simultaneous right ventricular and left ventricular pacing, from 5% to 12%. The list of important pacemaker characteristics and variables critical to pacemaker optimization is thus expanding. It is not unrealistic to expect that temporary perioperative biventricular pacing can evolve to a widely available tool that can increase cardiac output 15% to 20% in selected patients while decreasing myocardial oxygen consumption through improved mechanical efficiency. Having reviewed the manuscript, we submit the following questions:

First, what is the appropriate role for timing optimization in these studies? Second, do you use multisite pacing routinely in the operating room? Third, have you validated your three-dimensional synchrony index by linear regression against conventional echocardiographic indices and other measured variables? Fourth, was the synchrony index calculated by a technician blinded to the pacing condition?

I congratulate the authors again on their pioneering work and thank the Society for the privilege of discussion.

DR BACHA: Thank you, Dr Spotnitz, for your kind remarks. I will take the questions in order. Atrioventricular optimization was not done in this study for the following reasons. First of all, we wanted to keep it simple because some of these patients were studied in the operating room, some of these patients were studied in the postoperative period, sometimes while taking multiple inotropic agents. Atrioventricular optimization in a single-ventricle patient requires further study. It is unclear how you can best optimize a pacemaker in a single-ventricle patient, and therefore we did not want to introduce a variable that we could not control in this study.

On the routine use of multisite pacing, I would say the following. Before we start using it routinely, we want to perform a prospective randomized study studying multisite pacing as if it was an inotropic drug and determining whether we will end up with improved survival or at least a shortened hospital stay. So therefore before adopting it as a routine use in the operating room or in the postoperative period, we have started a prospective randomized study.

Validation of the three-dimensional echocardiographic technique has been done. I am not an expert on this, but it has been done with the usual two-dimensional indices of cardiac function as well as with magnetic resonance imaging cineangiography.

And in terms of calculating the synchrony index, each patient served as his or her control and therefore we could not blind the technician, because every patient was at baseline, not paced, and then after that, paced. It was the same technician who performed all the studies, trying to eliminate the human error that can be introduced in this kind of three-dimensional technical study.

Thank you very much.

	References

Top Abstract Introduction Patients and Methods Results Comment DISCUSSION References

 

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This Article Abstract Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Add to Personal Folders Download to citation manager Author home page(s): Emile A. Bacha Joanne P. Starr Permission Requests Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Bacha, E. A. Articles by Lang, R. M. Search for Related Content PubMed PubMed Citation Articles by Bacha, E. A. Articles by Lang, R. M. Related Collections Electrophysiology - arrhythmias