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European Journal of Heart Failure 2002 4(1):83-90; doi:10.1016/S1388-9842(01)00188-X
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© 2002 European Society of Cardiology

Echocardiographic prediction of long-term response to biventricular pacemaker in severe heart failure

Enis Oguza,*, Bahadir Dagdevirena, Tuba Bilsela, Osman Akdemirb, Izzet Erdinlera, Ahmet Akyola, Tanju Ulufera, Tuna Tezela and Kadir Gurkana

a Siyami Ersek Cardiovascular and Thoracic Surgery Center, Cardiology Clinic Istanbul, Turkey
b Trakya University, School of Medicine, Cardiology Department Edirne, Turkey

* Corresponding author. Murat Reis mah Demsel Sitesi C:21, 81200 Baglarbasi, Istanbul, Turkey; Tel.: +90-216-4928303; fax: +90-216-4180619. E-mail address: enisoguz1{at}superonline.com


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Biventricular pacing substantially improves LV systolic function and symptom status in some patients with dilated cardiomyopathy.

Aims: To assess whether the long-term benefit could be predicted from the echocardiographic parameters.

Methods and Results: Sixteen patients with dilated cardiomyopathy who underwent atrio-biventricular pacemaker implantation were analyzed in two groups: the responders (n=11) were those with a symptomatic improvement of one or more NYHA functional class; the non-responders (n=5) failed to improve at follow-up (7.6±5 months). Echocardiography was performed at baseline, the day after the implantation and then every 3 months. Besides the conventional parameters, the following variables were included: LV diastolic filling time (DFT); the duration of mitral regurgitation (dMR); and LV dP/dt obtained from the continuous wave mitral regurgitation curve. While the baseline DFT and dP/dt were not significantly different between non-responders and responders (256±105 vs. 358±115, P=0.14 and 564±199 vs. 468±117, P=0.44, respectively), the QRS width (149±15 vs. 175±24 ms, P=0.05) and the dMR (343±70 vs. 443±49 ms, P=0.007) were higher in the responders. The changes of dMR, DFT and QRS width by pacing were not significantly different between groups (P=0.18, 0.30 and 0.77, respectively). However, the change of LV dP/dt by pacing in the responders was significantly different than for non-responders (from 468±117 to 676±216 mmHg/s vs. from 564±199 to 483±94, P=0.002). An acute increase in LV dP/dt over 22% by pacing yielded only two false negatives and no false positives in predicting the long-term responsiveness.

Conclusion: Patients with longer QRS and dMR are more likely to benefit from atrio-biventricular stimulation. The acute changes of Doppler derived LV dP/dt may provide valuable information in predicting the long-term response to biventricular pacing.

Key Words: Biventricular pacing • Echocardiography • Heart failure

Received February 15, 2001; Revised May 22, 2001; Accepted August 10, 2001


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Biventricular pacing has recently been the subject of extensive investigation in patients with severe heart failure and intra- and interventricular conduction delay [1,2]. This new treatment modality is based on the hypothesis that the stimulation of both ventricles in order to resynchronize ventricular activation would enhance systolic performance [3]. Acute hemodynamic studies have revealed that atrio-biventricular pacing with a shortened atrioventricular interval substantially improves left ventricular (LV) systolic function in some patients with severe heart failure [4,5]. Nevertheless, it was reported that although some patients have benefited from this approach, others have not [6]. The observation of a variable efficacy of biventricular pacing has resulted in efforts to predict the response to this approach.

Basal QRS duration and LV+dP/dt that are thought as indirect markers of mechanical dyssynchrony have been reported as predictors for maximal pacing efficacy in acute hemodynamic studies [7–9]. However, identification of proper candidates for long-term benefit remains an important problem in clinical practice, particularly when considering such an invasive procedure with high cost. In the present study, we aimed to define the non-invasive parameters, which may be used both for predicting the long-term benefit before pacemaker implantation and for identifying the non-responder patients immediately after biventricular stimulation.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
2.1. Study population
The study group consisted of 16 consecutive patients who met the following criteria: (1) chronic and severe (NYHA class III–IV) heart failure for at least 6 months; (2) left ventricular end-diastolic diameter >55 mm and ejection fraction <40% on echocardiography; (3) refractory symptoms despite conventional drug treatment including ACE inhibitors, digoxin and diuretics; (4) maximum QRS duration >120 ms in patients with intrinsic conduction, or >200 ms in those with previously implanted with DDD pacemaker. The etiology of left ventricular systolic dysfunction was ischemic in 10 patients, idiopathic in five patients and previous aortic valve disease treated by valve replacement in one patient. Informed consent was obtained from all patients.

2.2. Evaluation of clinical status
The pre-implant evaluation included a review of medical history (recorded NYHA class), completion of a ‘quality of life’ questionnaire (‘Living with Heart Failure’ Questionnaire, University of Minnesota), and an exercise test with the Noughton protocol (except patients with NYHA class IV). These examinations were repeated every 3 months during the follow-up.

2.3. Pacemaker implantation
The left ventricle was paced with a specifically designed lead for pacing through the coronary sinus (Medtronic 2187 or 2188, Medtronic Inc., Minneapolis, MN). The left ventricular lead was placed at the anterolateral, lateral, or posterolateral wall in the site of the latest left ventricular depolarization. The right ventricle was paced with a passive-fixation or screw-in lead placed at the apex. The right atrial lead was placed in the right atrial appendage. Two different biventricular pacing systems were used: (1) the left and right ventricular leads were connected through a Y bifurcated adapter to the ventricular port of a conventional DDD pacemaker in four patients; (2) InSync three-chamber pacemaker system (Medtronic Inc., Minneapolis, MN) in 12 patients. After the implantation, pacemakers were programmed in AAI modes with lower rate of 45 bpm to provide intrinsic activity to be continued. To evaluate the acute changes, pacemakers were programmed in VDD mode with bipolar pacing/sensing and lower rate of 45 bpm at the day after the implantation.

2.4. Echocardiography
The examinations were performed by using HP Sonos 1500 (Hewlett–Packard; Andover, MA) system equipped with a 2.5-MHz phased array transducer. M-mode measurements of left ventricular dimensions were made according to the recommendations of the American Society of Echocardiography on parasternal long axis view [10]. Left ventricular volumes and ejection fraction were calculated by using Teicholz formula. Transmitral flow was recorded using pulsed wave Doppler from the apical four chamber view with the sample volume placed at the mitral valve leaflet tips. The diastolic filling time (DFT) was defined as the time interval between the beginning of E wave and the end of A wave. DFT values were corrected as per heart rate by using Bazett formula (corrected DFT=measured DFT/{surd}R–R interval).

Aortic velocity profile was obtained using pulsed wave Doppler from the apical five chamber view with the sample volume placed to the left ventricular outflow tract 0.5 cm below the aortic valve. Aortic velocity time integral was measured at baseline and during biventricular stimulation with variable AV delays in order to achieve optimized AV interval in each patient. We accepted the AV interval that was achieved maximal aortic velocity–time integral as optimal AV interval. The M mode and Doppler measurements were made on three consecutive cycles and the mean values were considered for statistical analysis. Echocardiographic examination was performed at baseline, the day after the implantation (30 min after AV delay optimization) and then every 3 months.

2.5. Echocardiographic measurement of LV dP/dt
Continuous wave Doppler tracing of mitral regurgitation jet was obtained on the apical four or two chamber views. Care was taken to align the imaging beam parallel to the direction of the regurgitant jet, and the gain, compress, wall filter and velocity scale settings were adjusted to obtain the clearest spectral Doppler trace. The duration of mitral regurgitation (dMR) was measured, and LV dP/dt was calculated from the CW Doppler trace with previously described ‘rate pressure rise’ method [11]. Briefly, the time interval of the velocity increase from 1 m/s to 3 m/s was measured on the CW Doppler trace. The pressure difference of these velocities (36–4 mmHg) according to Bernoulli equation (P=4V2) was divided to the corresponding time interval (Fig. 1).


Figure 1
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  		Fig. 1 Determination of Doppler-derived dP/dt from the continuous wave Doppler spectrum of MR jet in a patient before and after biventricular pacing: The horizontal lines represent 1m/s (4 mmHg) and 3 m/s (36 mmHg) and dashed lines time interval for 32 mmHg pressure change (36–4 mmHg). The T1 represents the time interval of the pressure change by intrinsic conduction and T2 by biventricular pacing. By pacing, an acute decrease in T corresponding increase with dP/dt can be noticed clearly.

 
2.6. Pacemaker follow-up
Biventricular pacing thresholds (at 0.5-ms pulse width), impedance (at 5-V amplitude and 0.5-ms pulse width) and biventricular sensing (mV) were measured at implantation, 1st week, 1st month, 3rd month, 6th month and, thereafter, every 6 months.

2.7. Reproducibility
An experienced echocardiographer who was unaware of the clinical status and pacing mode of the patient carried out the echocardiographic measurements. Two independent observers determined the inter-observer variability of the LV dP/dt measurement by comparing 10 randomly selected records. One observer repeating the same analysis 4 weeks later estimated the intra-observer variability. The reproducibility of these measurements was assessed by linear regression analysis and expressed as standard error of estimate (S.E.E.). Both the intra- and inter-observer variability were within acceptable limits (S.E.E.=3.5 and 4.3%, respectively).

2.8. Statistical analysis
Data are presented as mean±S.D. Mann–Whitney U test was used to compare the independent variables between the groups. Wilcoxon test was used to assess post-implant differences. Repeated measurement procedure providing analysis of variance when the same measurement is made several times on each subject, was used to compare acute changes of QRS duration, dMR, DFT and, dP/dt between groups by biventricular pacing. Statistical analysis was performed by using SPSS 7.5 software. Significance was set at P≤0.05.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
All study patients were male (mean age 59±10 years), and four of them were in NYHA functional class III and 12 in class IV. The mean QRS duration was 167±25 ms (ranges 124 to 205 ms). The mean LV ejection fraction was 25.8±8% (ranges 12–39%) and LV end-diastolic diameter was 70±8 mm (ranges 57–81 mm). All patients had left bundle branch block. The mean follow-up duration was 7.6±5 months (range 3–18 months). The mean biventricular-pacing threshold was 1.5±0.8 V at implantation and 2.1±1.1 V at the end of follow-up. All patients paced effectively during follow-up. PR intervals, optimized AV delays, basal aortic VTI and optimized aortic VTI are given in Table 1. Aortic VTIs acutely increased in all patients except one patient by AV delay optimization (from 12.7±4.3 to 15.5±4.2 cm, P=0.001). Atrio-biventricular pacing resulted in: significant shortening of QRS duration; improvement of symptoms and exercise capacity (Table 2); increase of LV ejection fraction; LV dP/dt and DFT; and decrease of LV systolic and diastolic dimensions (Table 3) at the end of follow-up. The decrease in dMR was not statistically significant (P=0.18).


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  		Table 1 AV delay optimization

 


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  		Table 2 Clinical variables and QRS duration at baseline and at the end of follow-up

 


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  		Table 3 Echocardiographic variables at baseline and at the end of follow-up

 
Three patients died in the hospital because of the worsening of heart failure in the 3rd month. We obtained their QoL score and NYHA class data during hospital admission. Two patients with NYHA Class IV did not show any symptomatic improvement during follow-up. These five patients were considered as non-responders (Group I). Group II (responders) included the remaining 11 patients who showed marked improvement according to their NYHA class, exercise tolerance, quality of life and echocardiographic parameters.

In the non-responder group, a left ventricular electrode was implanted into the anterolateral vein in one patient, into the lateral vein in two patients and into the posterolateral vein in two patients. In the responder group, a left ventricular electrode was implanted into the anterolateral vein in four patients, into the lateral vein in five patients and into the posterolateral vein in two patients. At baseline, the groups were comparable in their PR interval, LV end-diastolic diameter, LV ejection fraction, DFT and LV dP/dt. However, QRS duration (175±24 and 149±15 ms, P=0.05), and dMR (443±49 and 343±70 ms, P=0.007) were higher in the responder-group (group II) (Table 4). When we analyzed the individual data, the baseline QRS durations showed significant overlapping between groups (Fig. 2a). The baseline dMR values >405 ms (the lower limit of 95% confidence interval of responder group) yielded one false positive and two false negatives for predicting long-term responsiveness to pacing (Fig. 2b).


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  		Table 4 The mean values of baseline echocardiographic variables and QRS duration in responder and non-responder groups

 


Figure 2
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  		Fig. 2 (a) Scatter plot showing the baseline QRS duration in responder and non-responder patients. (b) Scatter plot showing the baseline duration of the mitral regurgitation in responder and non-responder patients.

 
The mean LV dP/dt was increased by pacing in the responder group (468±117/676±216 mmHg/s, P=0.008), while it was unchanged in the non-responders (564±199/483±94 mmHg/s, P=0.14). This acute LV dP/dt-rise was determined as the single finding that significantly differentiates both groups (P=0.002) (Fig. 3). An acute increase in dP/dt over 22% (the lower limit of 95% confidence interval of responder group) by pacing yielded only two false negatives and no false positive result in predicting the long-term responsiveness (Fig. 4).


Figure 3
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  		Fig. 3 Scatter plots demonstrating the acute changes of: the LV dP/dt; diastoling filling time (DFT); QRS duration; and duration of mitral regurgitation (dMR) by pacing in group I (non-responders) and group II (responders). P values refer to Repeated Measurement Analysis which compares two groups in regard to their related dependent variables changing by pacing. The LV dP/dt-rise was the single variable significantly different between groups.

 


Figure 4
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  		Fig. 4 Scatter plot showing percent changing of the LV dP/dt in responder and non-responder patients by pacing. The horizontal line representing the cut-point of 22% was defined as the lower limit of 95% confidence interval of the responder patients.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Our study demonstrated that patients with severe heart failure benefit from biventricular stimulation as shown by: a decrease of QRS duration; improvement of symptoms and exercise capacity; enhanced systolic function; and decreased LV dimensions. The major findings of the study were: (1) The baseline durations of QRS and mitral regurgitation were longer in responder patients; and (2) The Doppler derived acute LV dP/dt-rise was the most significant predictor of the long-term response to biventricular pacing in our study population.

The lack of benefit from standard dual chamber pacing may be due to the undesired changing of ventricular activation sequence and discoordinated contraction created by the stimulation of right ventricular apex [12,13]. Therefore, it was hypothesized that the stimulation of both ventricles to resynchronize the ventricular activation would enhance the systolic performance; and biventricular pacing has recently been a subject of investigation in patients with severe heart failure and intraventricular conduction delay. The results of biventricular pacing seem to be more promising than conventional dual chamber pacing. Nevertheless, it has been reported that although some patients have benefited from this approach, others have not [6].

It was previously reported that in patients with dilated cardiomyopathy, there is a strong linear correlation between the durations of QRS and mitral regurgitation [3]. This finding was explained with the increased duration of systole due to impaired mechanical synchronization [3]. In addition, the acute hemodynamic response to left ventricular based pacing demonstrated that wider baseline QRS was associated with greater LV systolic improvement. In our study population the responder group had longer baseline duration of QRS and mitral regurgitation consistent with the hypothesis that patients with relatively more impaired ventricular synchronization would be more likely benefit from biventricular pacemakers.

Nelson et al. [9] reported that catheter derived baseline LV dP/dtmax inversely correlates with the amount of changes in LV dP/dtmax and pulse pressure with acute LV based pacing; and combining that with basal QRS duration enhances the predictive accuracy for identifying the responsive patients. We observed, however, that although the mean Doppler derived LV dP/dt was lower in responders (468±117/564±199), the difference was not statistically significant. Alonso et al. [6] reported that QRS narrowing by biventricular pacing was more often observed in patients having long-term benefit. However, we found QRS narrowing in all patients except one responder in spite of five patients having had no long-term clinical and mechanical improvement.

The improvement of LV dP/dt by biventricular stimulation was previously reported to reflect the short-term benefit in hemodynamic studies [7–9]. Nevertheless, the value of this finding in predicting the long-term response has not yet been clarified. Our results suggested that the increase in LV dP/dt by biventricular pacing has a high ability to discriminate long-term responders from non-responders.

The increased LV diastolic filling time due to optimization of the timings of left atrial and left ventricular contractions [14] and the shortened systole [15] were mentioned among the mechanisms explaining the benefit from atrio-biventricular pacemakers. Porciani et al. [15] showed that a decrease in interventricular delay, which is the time difference between the onset of pulmonic and aortic flow, provided by biventricular stimulation played an important role in the hemodynamic improvement. They also reported that there was no correlation between baseline QRS duration and interventricular delay nor between narrowing in QRS by biventricular stimulation and decrease in interventricular delay. These findings point out that the interventricular conduction delay is more important than intraventricular conduction delay. TEI-index, defined as the sum of left ventricular isovolumetric contraction and relaxation time divided by left ventricular ejection time, is a myocardial performance index involving both systolic and diastolic functions [16]. It has been shown that biventricular pacing significantly decreased the left ventricular myocardial performance index [15]. However, the decrease in left ventricular myocardial performance index was associated with no significant difference in left ventricular isovolumetric relaxation time/left ventricular ejection time. In our study, the biventricular stimulation with optimized AV interval resulted in prominent prolongation of LV filling time both in responder and non-responder groups; however patients with increased LV dP/dt by pacing showed long-term benefit. All of these findings, as in other invasive hemodynamic study [8], led us to interpret that biventricular stimulation could affect left ventricular systolic functions more than diastolic functions.

We also found a significant reduction of LV dimensions at long-term follow-up, suggesting that the resynchronization therapy could possibly provide a favorable effect upon the ventricular remodeling in patients with severe heart failure and intraventricular conduction delay.

4.1. Limitations
The study was conducted on a limited number of patients and these findings need to be confirmed in larger groups. Nevertheless, to the best of our knowledge, this work is the first in the literature to relate the symptomatic improvement to the hemodynamic parameters obtained from echocardiography at baseline, short- and long-term periods. It was previously reported that LV dP/dt obtained from catheterization and echocardiography correlates well with each other [11]. Furthermore, echocardiographic dP/dt was shown to be a powerful predictor of event-free survival in patients with dilated cardiomyopathy [17]. However, the sensitivity of echocardiographic approach in reflecting the dP/dt changes after biventricular stimulation is not clear. In our study, the intra- and interobserver variability of the echocardiographic dP/dt-measurement were found to be within acceptable limits. But as was the case in two of our patients, the CW Doppler tracing of mitral regurgitation could be of sub-optimal quality in some individuals.

In conclusion, patients with severe congestive heart failure and with relatively longer QRS and mitral regurgitation durations are more likely to benefit from biventricular pacemakers. The evaluation of acute changes of Doppler derived LV dP/dt by pacing may provide valuable information in predicting the long-term response to atrio-biventricular stimulation.


   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 

  1. Cazeau S., Ritter P., Lazarus A., et al. Multisite pacing for end-stage heart failure: early experience. Pacing Clin Electrophysiol (1996) 19:1748–1757.[CrossRef][Medline]
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  3. Xiao H.B., Brecker S.J., Gibson D.G. Effects of abnormal activation on the time course on the left ventricular pressure pulse in dilated cardiomyopathy. Br Heart J (1992) 68:403–407.[Abstract/Free Full Text]
  4. Blanc J.J., Etienne Y., Gilard M., et al. Evaluation of different ventricular pacing sites in patients with severe heart failure: results of an acute hemodynamic study. Circulation (1997) 96:3273–3277.[Abstract/Free Full Text]
  5. Leclercq C., Cazeau S., Le Breton H., et al. Acute hemodynamic effects of biventricular DDD pacing in patients with end-stage heart failure. J Am Coll Cardiol (1998) 32:1825–1831.[Abstract/Free Full Text]
  6. Alonso C., Leclercq C., Victor F., et al. Electrocardiographic predictive factors of long-term clinical improvement with multisite biventricular pacing in advanced heart failure. Am J Cardiol (1999) 84:1417–1421.[CrossRef][Web of Science][Medline]
  7. Auricchio A., Stellbrink C., Block M., et al. Effect of pacing chamber and atrioventricular delay on acute systolic function of paced patients with congestive heart failure. Circulation (1999) 99:2993–3001.[Abstract/Free Full Text]
  8. Kass D.A., Chen C.-H., Curry C., et al. Improved left ventricular mechanics from acute VDD pacing in patients with dilated cardiomyopathy and ventricular conduction delay. Circulation (1999) 99:1567–1573.[Abstract/Free Full Text]
  9. Nelson G.S., Curry C.T., Wyman B., et al. Predictors of systolic augmentation from left ventricular preexitation in patients with dilated cardiomyopathy and intraventricular conduction delay. Circulation (2000) 101:2703–2709.[Abstract/Free Full Text]
  10. Sahn D.J., DeMaria A., Kisslo J., Weyman A. The Committee on M-mode Standardization of the American Society of Echocardiography: recommendations regarding quantitation in M-mode echocardiography: results of a survey of echocardiographic measurements. Circulation (1978) 58:1072–1083.[Abstract/Free Full Text]
  11. Bargiggia G.S., Bertucci C., Recusani F., et al. A new method for estimating left ventricular dP/dt by continuous wave Doppler echocardiography. Circulation (1989) 80:1287–1292.[Abstract/Free Full Text]
  12. Gold M.R., Feliciano Z., Gottlieb S.S., et al. Dual-chamber pacing with a short atrio-ventricular delay in congestive heart failure: a randomized study. J Am Coll Cardiol (1995) 26:967–973.[Abstract]
  13. Linde C.L., Gadler F., Adner M., et al. Results of atrioventricular synchronous pacing with optimized delay in patients with severe congestive heart failure. Am J Cardiol (1995) 75:919–923.[CrossRef][Web of Science][Medline]
  14. Nishimura R.A., Hayes D.L., Holmes D.R., et al. Mechanism of hemodynamic improvement by dual-chamber pacing for severe left ventricular dysfunction: an acute Doppler and catheterization hemodynamic study. J Am Coll Cardiol (1995) 25:281–288.[Abstract]
  15. Porciani M.C., Puglisi A., Colella A., et al. Echocardiographic evaluation of the effect of biventricular pacing: the InSync Italian Registry. Eur Heart J (2000) 2:J23–J30.
  16. Tei C. New noninvasive index for combined systolic and diastolic ventricular function. J Cardiol (1995) 26:135–136.[Web of Science][Medline]
  17. Kolias T.J., Aaronson K.D., Armstrong W.F. Doppler-derived dP/dt and –dP/dt predict survival in congestive heart failure. J Am Coll Cardiol (2000) 36:1594–1599.[Abstract/Free Full Text]

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