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(Circulation. 2004;109:2544-2549.)
© 2004 American Heart Association, Inc.

Clinical Investigation and Reports

Electrical and Mechanical Components of Dyssynchrony in Heart Failure Patients With Normal QRS Duration and Left Bundle-Branch Block

Impact of Left and Biventricular Pacing

Mark S. Turner, MRCP; Rob A. Bleasdale, MRCP; Dragos Vinereanu, MD; Catherine E. Mumford; Vince Paul, MD, FRCP; Alan G. Fraser, FRCP; Michael P. Frenneaux, MD, FRCP

From the Wales Heart Research Institute (M.S.T., R.A.B., D.V., C.E.M., A.G.F., M.P.F.), Cardiff, and St Peter’s Hospital (V.P.), Chertsey, UK.

Correspondence to Michael P. Frenneaux, MD, FRCP, Professor of Cardiology, Wales Heart Research Institute, University of Wales College of Medicine, Heath Park, Cardiff CF14 4XN, UK. E-mail scaccia{at}cf.ac.uk

Received November 24, 2003; revision received February 10, 2004; accepted February 11, 2004.

	Abstract

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
Background— Resynchronization pacing is an effective symptomatic treatment for heart failure patients with prolongation of the QRS duration (QRSd). Dyssynchronous contraction of the left ventricle is also observed with normal QRSd. We set out to determine how electrical activation of the left ventricular (LV) free wall differed between patients with left bundle-branch block (LBBB) and normal QRSd and if synchrony improved during pacing in patients with normal QRSd.

Methods and Results— Twenty-two patients were implanted with resynchronization pacemakers, 13 with LBBB (mean QRS, 171 ms) and 9 with normal QRSd <120 ms (mean, 100 ms). LV lead electrograms and surface ECGs in sinus rhythm (unpaced) were recorded. Conventional and tissue Doppler echocardiography were performed without pacing, with LV and biventricular pacing at optimal atrioventricular delay. Lead electrograms from the LV free wall were later in the LBBB patients in absolute terms (155 ms [SD 23] versus 65.5 ms [SD 25]; P=0.05) and also relative to the surface QRS (90.5% [SD 8] versus 65.5% [SD 24]). Improved synchrony of the left and right ventricles (interventricular synchrony) and of the LV myocardial segments (intraventricular synchrony) was observed for patients with LBBB and normal QRSd. Baseline LV synchrony correlated with timing of LV free-wall electrical activation. Improved intraventricular synchrony during pacing also correlated with LV free-wall electrical activation time.

Conclusions— Resynchronization of systole can be achieved for patients with normal QRSd and LBBB during biventricular and LV pacing. The timing of LV free-wall electrical activation correlated with the improvement in synchrony.

Key Words: bundle-branch block • pacing • contractility • heart failure

	Introduction

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
Cardiac resynchronization therapy has been shown to improve hemodynamic parameters, exercise capacity, symptoms, and quality of life and also to reduce hospitalization among patients with heart failure who have prolongation of the QRS duration.^1,2 A meta-analysis of trials also suggested that resynchronization can reduce mortality, although this awaits confirmation.³ The mechanisms responsible are believed to include improved synchrony of the timing of left and right ventricular (RV) systole (interventricular synchrony), improved synchrony of the different segments of the left ventricle (intraventricular synchrony), optimization of the atrioventricular delay (AVD), and a reduction in mitral regurgitation.^4–7

Detailed echocardiographic assessment using tissue Doppler echocardiography has shown that patients with left bundle-branch block (LBBB) have marked intraventricular dyssynchrony that can be improved by biventricular pacing.⁶ In a tissue Doppler echocardiographic study, it was shown that heart failure patients with normal QRS duration also have dyssynchronous left ventricular (LV) contraction compared with individuals with normal ventricular function.⁸

So far in chronic randomized controlled trials of clinical end points, biventricular pacing has been the predominant pacing mode tested. However, LV pacing provides similar or greater acute hemodynamic improvement,⁹ and data have recently been presented from the PAcing THerapies for Congestive Heart Failure (PATH-CHF) II study confirming long-term benefits from LV pacing among patients with QRS duration >120 ms.¹⁰ In a previous study of patients implanted with resynchronization pacemakers, the optimal pacing mode (as determined by acute improvement in contractility) was at least as often LV pacing as biventricular.¹¹ In a dog model of heart failure associated with LBBB, LV and biventricular pacing improved mechanical synchrony in a similar way, although the pattern of electrical activation was quite different. LV pacing did not reduce overall electrical activation time, whereas biventricular pacing reduced it significantly.¹² Our study assesses the impact of LV pacing and biventricular pacing on dyssynchrony, electrical activation pattern, and electromechanical coupling in heart failure patients with normal and prolonged QRS duration.

	Original Hypotheses

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
Our first hypothesis was that the pattern of electrical activation in heart failure patients with normal QRS duration differs from that among patients with LBBB. Our second hypothesis was that LV pacing and biventricular pacing can improve mechanical synchrony in patients with normal QRS duration in a similar manner to that seen in patients with LBBB.

We studied the effects of resynchronization (by LV pacing and biventricular pacing) in heart failure patients with LBBB and in patients with a normal QRS duration. The aims of the study were to assess the contribution of electrical versus mechanical components of dyssynchrony and to evaluate the impact of pacing in patients with a normal QRS duration. The electrical activation time of the free wall of the left ventricle was measured by recording an electrogram from the tip of the LV lead and the impact of pacing on interventricular, and intra-LV synchrony was evaluated by conventional and tissue Doppler echocardiography.

	Methods

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
We studied 22 patients with severe heart failure who had NYHA class III or IV symptoms; 9 patients had a normal QRS duration (<120 ms), and 13 patients had a prolonged QRS duration and LBBB and met standard implantation criteria.¹³ The project was approved by the local research ethics committee, and the patients gave written informed consent.

The patients had a mean age of 63.6 years (range, 49 to 75). Fourteen had dilated cardiomyopathy. In 8 of the patients, heart failure had an ischemic etiology. Nineteen of the patients were male, and the mean NYHA class was 3.2. Pacing systems were implanted by standard transvenous techniques, including a coronary sinus venogram to delineate the venous anatomy. Sixteen patients received InSync III pacemakers (Medtronic Inc) capable of pacing in either LV or biventricular mode. Five patients had a Kappa pacemaker (Medtronic Inc) capable of only atrio-LV pacing, and 1 patient had an InSync (Medtronic Inc) capable of only biventricular pacing. Because the hemodynamic benefits of pacing depend on the LV lead being placed on the free wall of the left ventricle, we excluded 1 patient from the study where a great cardiac vein position was accepted.

Atrioventricular Delay
The optimal AVD was determined using transmitral flow profiles, as previously described.¹⁴ Programmed AVD ranged from 90 to 110 ms, mode 100 ms.

Measurement of Electrical Activation of the Free Wall of the Left Ventricle
LV lead electrogram was recorded using the device programmer, while pacing was suspended. An electrogram from the lead recorded during a sinus beat was compared with a simultaneously recorded surface ECG. The time of LV free-wall activation measured from the onset of the QRS complex was compared with total duration of the surface QRS complex. The ratio of the delays from surface QRS onset to LV free-wall activation and surface QRS duration was calculated. The pattern of electrical activation of the patients with a normal QRS duration was compared with those with LBBB.

Pacemaker Programming for Echocardiography
The pacemaker was switched to backup mode (VVI at 30 beats per minute, so that no pacing therapy was delivered), and after 10 minutes of rest, a detailed transthoracic echocardiographic study was performed. The pacemaker was then reprogrammed to VDD-LV mode, and the echocardiographic study was repeated after another 10-minute period of stabilization. Finally, the pacemaker was reprogrammed to VDD-biventricular mode (LV stimulation was programmed to occur 4 ms before RV stimulation for the 16 patients with InSync III pacemakers), and echocardiography was performed again after an additional 10-minute period of stabilization. Heart rate was measured during each stage. The ECG was recorded simultaneously.

Echocardiography
Patients were studied in the left lateral decubitus position using a commercially available ultrasound system equipped with tissue Doppler (Vingmed System 5, GE Vingmed) using a 1.5- to 2.5-MHz transducer. Digital echocardiographic data were acquired during passively held end expiration.

Standard Echocardiographic Studies
The study consisted of cross-sectional and Doppler blood flow measurements. LV ejection fraction was calculated by the modified biplane Simpson’s method. LV filling time was measured from pulsed-wave Doppler recording of the transmitral flow. The severity of secondary mitral regurgitation was estimated in an apical 4-chamber view by measuring the width of the vena contracta¹⁵ and by calculating the regurgitant orifice area using the proximal isovelocity surface area method.¹⁶

Tissue Doppler Echocardiography
Five standard imaging planes were acquired: parasternal long-axis (PLAX view), parasternal short-axis, apical 4-chamber, apical 2-chamber, and apical long-axis views. Myocardial velocities and timings were measured offline (Echopac TVI, GE Vingmed) from 6 LV myocardial segments and 1 RV segment. Time-to-peak systolic velocity was measured from the beginning of the QRS complex to the peak systolic velocity, and intra-LV synchrony was defined as the standard deviation of the time-to–peak systolic velocity in these 6 myocardial segments.⁷ Interventricular synchrony was defined as the difference between RV and 6-site mean LV longitudinal timings. We have reported detailed studies of interobserver agreement of tissue Doppler measurements in our laboratory.¹⁷

Statistical Analysis
Statistical analysis was performed with SPSS software (version 11.0) (SPSS Inc). Results are presented as mean±SD. Paired Student’s t testing was used for comparisons between no pacing and the different pacing modes. P<0.05 for a 2-tailed test was considered significant.

	Results

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Timing of LV Free-Wall Electrical Activation
Surface QRS duration ranged from 79 to 120 ms (mean, 100 [SD 18]) in the normal QRS duration group and 140 to 218 ms (mean, 171 [SD 23]) (P<0.001) in the LBBB group. Electrograms recorded from the LV lead during implantation and from the programmer after generator implantation are shown in Figure 1. LV free-wall activation occurred earlier in the normal QRS duration group than in the LBBB group (65.5 ms [SD 25] versus 155 ms [SD 23] after the onset of surface QRS complex, P<0.001) (Figure 2). This difference remained significant when the timing of LV free-wall activation was expressed in terms of a percentage of surface QRS complex duration. In the LBBB group, the LV free-wall activation occurred near the end of the QRS complex, 90.5% (SD 8) through the QRS complex (range, 77% to 102%), whereas it occurred 65.5% (SD 24) through the surface QRS complex (range, 23% to 99%) in the patients with a normal QRS duration (P<0.05). This suggests an overall difference between the patients with LBBB, where LV free-wall activation is late, and those with normal QRS durations, where it was significantly earlier on average. However, in the patients with normal QRS duration, there was a wide range of free-wall activation times. Three of the patients had LV free-wall activation in the last 15% of the surface QRS–occult electrical dyssynchrony, being qualitatively similar to the LBBB patients.

View larger version (55K): [in this window] [in a new window]   Figure 1. Representative example of a surface ECG measured simultaneously with an electrogram taken from the LV lead tip. A, Recording taken during implantation from the PSA (Medtronic). B, Recording taken through the programmer (Medtronic) in the same patient after implantation of the device. Line A confirms that the 2 panels are lined up on the R wave of the ECG. Line B confirms that the measured timing point coincides with that measured in panel A. This represents the LV free-wall activation time.

View larger version (12K): [in this window] [in a new window]   Figure 2. Graphical representation of LV free-wall activation time compared with the surface QRS duration. It can be seen that the mean free-wall activation time for patients with normal QRS duration is two thirds of the way through the total QRS and that the standard deviation is high, indicating wide variation in the LV free-wall timing in this group. In contrast, the patients with LBBB have later LV free-wall activation both in absolute terms (P<0.01) and relative to the total QRS duration (P<0.05).

Baseline Synchrony by Tissue Doppler Echocardiography
The baseline synchronicity index of the LV correlated with the timing of LV free-wall activation time when the latter was expressed in absolute terms and as a proportion of the surface QRS duration, as shown in Figure 3, A and B, respectively.

View larger version (22K): [in this window] [in a new window]   Figure 3. LV free-wall activation time is plotted against the baseline synchronicity index calculated from tissue Doppler measurement of time-to-peak velocity in 6 myocardial segments. There is a correlation between the electrical activation timing of the LV free wall and the amount of dyssynchrony (A). This relationship was maintained when the free-wall timing was expressed as a proportion of the surface QRS duration (B).

Improvements in Ventricular Function and Synchrony During Pacing
Patients with normal QRS duration improved clinically from NHYA class 3.4 (0.5) to 1.8 (0.4) (P<0.001). Patients with LBBB also improved from NYHA class 3.0 (0.4) to 2.0 (0.7) (P<0.001). As has been previously reported in the patients with prolongation of QRS duration, we detected significant improvements in the interventricular timing, intra-LV synchrony, and LV ejection fraction with both left and biventricular pacing compared with the nonpaced values. A summary of the effects of pacing on the 2 groups is shown in Tables 1 and 2. The effects of pacing on the 2 groups did not differ significantly. Significant changes were seen in the patients with normal QRS duration in terms of interventricular timing and intraventricular synchrony in both LV and biventricular pacing. The effect of pacing on synchronicity was similar in patients with LBBB and the normal QRS duration (Figure 4). This was despite the electrographic evidence that the LV free-wall activation was significantly earlier, on average, in the group with normal QRS duration, both in qualitative (relative to surface QRS) and absolute terms. The effect of LV and biventricular pacing on the different myocardial segments is shown in Figures 5 and 6 . Both pacing modes synchronize the LV contraction. LV pacing seems to delay the RV contraction to a greater extent than biventricular pacing.

View this table: [in this window] [in a new window]   TABLE 1. Effect of LV Pacing

View this table: [in this window] [in a new window]   TABLE 2. Effect of Biventricular Pacing

View larger version (13K): [in this window] [in a new window]   Figure 4. Graphs show the synchronicity index at baseline and during left and biventricular pacing. LV synchronicity index is improved in both patient groups by both pacing modalities.

View larger version (22K): [in this window] [in a new window]   Figure 5. Mean time-to-peak velocity for the 6 LV myocardial segments and 1 RV at rest and during LV pacing. During LV pacing, the RV contraction is later and the LV segments contract more synchronously.

View larger version (20K): [in this window] [in a new window]   Figure 6. Mean time-to-peak velocity for the 6 LV myocardial segments and 1 RV at rest and during biventricular pacing. A similar effect as in Figure 5 is shown for biventricular pacing, but with less delay in the RV contraction. The change after pacing is similar for all patients; the patients with normal QRS duration have less LV dyssynchrony at baseline but achieve a more synchronous contraction with pacing. The effect on RV contraction was similar in both groups. There was no statistical difference in the effect of pacing in the 2 groups.

Improvement in Synchrony With Pacing
The improvement in intraventricular synchrony after pacing also correlated with the timing of LV free-wall activation when expressed in absolute terms or relative to the surface QRS duration, as shown in Figure 7, A and B, respectively.

View larger version (24K): [in this window] [in a new window]   Figure 7. Plots represent the optimal change in LV synchrony (left or biventricular) versus the baseline LV free-wall activation time expressed in milliseconds (A) and relative to the total QRS duration (B). There is a correlation between the improvement in synchrony from pacing and LV free-wall activation timing, such that a greater improvement is seen in patients with late LV free-wall electrical activation. This also shows a more heterogeneous response to pacing in the patients with normal QRS duration than in those with LBBB. However, most of the patients with normal QRS duration demonstrate improved LV synchrony in a similar way to those with LBBB.

	Discussion

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
The important findings of this study were, first, that the electrical activation pattern differs significantly between heart failure patients with normal QRS duration and that seen in patients with LBBB. However, some patients with normal QRS duration also had late LV free-wall activation relative to the surface QRS, suggesting that these patients had heterogenous patterns of electrical activation. Second, despite these differences, LV and biventricular pacing can resynchronize mechanical function of the left ventricle in both patient groups. The mean timing of LV free-wall activation among the patients with heart failure with normal QRS duration was consistent with that reported for the normal human heart, where the LV free-wall is activated in the latter half of the activation sequence.¹⁸ Third, the heart failure patients with normal QRS durations nevertheless had mechanical dyssynchrony compared with published values for healthy controls.⁸ This suggests that, in addition to the presence of delayed free-wall electrical activation in some patients, there is also a disturbance of electromechanical coupling that may contribute to the mechanical dyssynchrony observed in patients with normal QRS duration.

Although there is some correlation between QRS duration and severity of heart failure, there are still many patients with NYHA class III or IV heart failure symptoms who have a normal QRS duration. Some of these may have relatively late LV free-wall electrical activation in addition to the possibility of delayed electromechanical coupling. It has been shown that there is a high prevalence of LV dyssynchrony in heart failure patients with a normal QRS duration using both tissue Doppler echocardiography⁸ and radionuclide ventriculography techniques.⁵ We have previously shown that LV pacing can have acute hemodynamic benefits for patients with a normal QRS duration (<120 ms), but this benefit was seen predominantly in patients who had a resting pulmonary capillary wedge pressure >15 mm Hg.¹⁹ As well as occult electrical dyssynchrony (delayed electrical activation of the LV free wall despite normal surface QRS durations) and delayed electromechanical coupling, pacing therapy may also work by mechanisms other than improvement of LV intraventricular synchrony in these patients.²⁰

In the present study, we have shown that LV free-wall activation occurs earlier overall in heart failure patients with normal QRS duration compared those with LBBB, and the timing of free-wall activation in most patients with a normal QRS duration was similar to that previously reported in healthy hearts. These data support occult conduction delay of the free wall of the left ventricle in some of the patients; however, the observed improvements in patients with early LV free-wall activation make it unlikely to be the sole reason for improved synchrony. Most of the group with normal QRS duration has a substantially different electrical activation pattern rather than simply having faster conduction compared with the LBBB patients. Advancing electrical activation may, however, still be relevant, because pacing the free wall of the LV will advance electrical activation even in normal hearts, where the activation time is similar to that observed in our heart failure patients with normal QRS durations.

The novel additional finding of this study was that intraventricular synchrony (as well as other echocardiographic parameters) was improved in heart failure patients with normal QRS duration by both LV and biventricular pacing. In addition, there was a correlation between baseline synchrony and the electrical timing of the LV free wall. The magnitude of improvement in synchrony with pacing also correlated with the baseline free-wall activation time. Thus, some patients with a normal QRS duration may also derive benefits from resynchronization pacing, and the timing of LV free-wall electrical activation may help to identify those who will be resynchronized.

These findings also suggest that the underlying pathophysiology of heart failure may lead to LV intraventricular dyssynchrony by mechanisms other than electrical conduction delay, consistent with the observations of Yu et al.⁸ Significant changes in interventricular timing whereby LV contraction was advanced compared with the right ventricle, making contraction of the 2 ventricles more synchronous, were also observed after pacing. The baseline synchrony was very similar to that previously reported for patients with heart failure,⁸ and the effects of pacing on mechanical synchrony (both intraventricular synchrony and interventricular synchrony) were similar whether the patient had LBBB or a normal QRS duration.

Recent experimental data in a dog model have shown that LV free-wall pacing can improve the synchrony of mechanical contraction just as effectively as biventricular pacing.¹² This is a particularly important observation because these investigators simultaneously demonstrated that LV pacing produced no reduction in the duration of electrical activation (although reversing its direction), in contrast to a marked reduction in activation time with biventricular pacing. Although these data were obtained in an LBBB model, they conclusively show that there is discordance between electrical activation and mechanical synchrony. Our findings in patients with heart failure would support the conclusions of this animal study.

Our present findings suggest that patients with heart failure in NYHA class III or IV with a normal QRS duration can demonstrate resynchronization from coronary sinus–based pacing. The major limitation of this study is that it does not provide blinded data on clinical end points. A much larger trial is needed to evaluate the effect of resynchronization therapy in patients with heart failure and a normal QRS duration on clinical end points such as exercise capacity, quality of life, and hospitalization.

Clinical Implications
These findings suggest that resynchronization therapy may be beneficial for heart failure patients with normal QRS durations as well as for those with LBBB.

	Conclusion

Top Abstract Introduction Original Hypotheses Methods Results Discussion Conclusion References

 
The important clinical conclusion of this study is that heart failure patients with a normal QRS duration can have improved ventricular synchrony after resynchronization pacing. In some patients, this may be attributable to the presence of occult electrical dyssynchrony but may also be attributable to improved electromechanical coupling. Long-term studies using clinical end points of cardiac resynchronization should be undertaken in heart failure patients with normal QRS durations.

	Acknowledgments

 
M. Turner was supported by a Bristol-Myers Squibb Cardiovascular Fellowship. R.A. Bleasdale, C.E. Mumford, and Dr Frenneaux were supported by the British Heart Foundation.

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