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European Journal of Heart Failure 2008 10(5):507-513; doi:10.1016/j.ejheart.2008.03.006
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© 2008 European Society of Cardiology

Effect of biventricular pacing on symptoms and cardiac remodelling in patients with end-stage hypertrophic cardiomyopathy

Dominic P.S. Rogersa, Stefania Maraziaa, Anthony W. Chowa, Pier D. Lambiasea, Martin D. Lowea, Michael Frenneauxb, William J. McKennaa and Perry M. Elliotta,*

a The Heart Hospital, University College London UK
b Department of Cardiovascular Medicine, University of Birmingham UK

* Corresponding author. The Heart Hospital, 16-18 Westmoreland St, London W1G 8PH, UK. Tel.: +44 2075738888x4801; fax: +44 2075738838. E-mail addresses: minirogers{at}googlemail.com (D.P.S. Rogers), pelliott{at}doctors.org.uk (P.M. Elliott).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Conflict of interest
 References
 
Background: Biventricular (BiV) pacing is an established therapy for heart failure in ischaemic and dilated cardiomyopathy. Its effects in end-stage hypertrophic cardiomyopathy (HCM) are unknown.

Aims: To assess the potential benefits of BiV pacing in patients with symptomatic end-stage HCM.

Methods: Twenty patients with non-obstructive HCM (12 male, mean age 57±13 years), left bundle branch block and symptoms of heart failure refractory to medical therapy underwent implantation of a BiV device. NYHA class, echocardiographic parameters and exercise capacity were assessed before and after implantation.

Results: At a mean follow-up of 13±6 months, an improvement of at least one NYHA class was reported in 8 (40%) patients. A clinical response was associated with an increase in ejection fraction (from 41±14% to 50±12%, p=0.009), and reductions in left ventricular end-diastolic diameter (from 57±6 mm to 52±7 mm, p=0.031) and left atrial diameter (from 65±8 mm to 57±6 mm, p=0.005). Percentage predicted peak oxygen consumption was unchanged in responders but significantly declined in non-responders (p=0.029).

Conclusions: BiV pacing improved heart failure symptoms in a significant proportion of patients with end-stage HCM. Symptomatic improvement was associated with reverse remodelling of the left atrium and ventricle.

Key Words: Hypertrophic cardiomyopathy • Biventricular pacing • Remodelling • Heart failure • Cardiac resynchronisation

Received June 27, 2007; Revised December 27, 2007; Accepted March 12, 2008


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Conflict of interest
 References
 
Hypertrophic cardiomyopathy (HCM), the commonest inherited heart muscle disease, is characterized by myocardial hypertrophy and myofibrillar disarray. The clinical course of HCM varies widely between individuals [1,2] but in up to 10% of patients progressive myocardial fibrosis leads to the development of systolic dysfunction and congestive cardiac failure [3]. There are currently limited therapeutic options for this ‘end-stage’ disease which, despite pharmacological therapy, often results in cardiac transplantation or death from refractory heart failure or ventricular arrhythmias [4,5].

Biventricular (BiV) pacing is an established adjunctive treatment for patients with ischaemic or dilated cardiomyopathy, symptomatic heart failure and left bundle branch block (LBBB). The rationale for this therapy is to reduce mechanical dyssynchrony leading to enhanced contractile performance and improved diastolic filling. Randomised controlled trials have demonstrated that BiV pacing can reduce symptoms of heart failure, increase exercise capacity, reduce hospitalisations and improve prognosis [6-8], but the efficacy of BiV pacing in HCM is unknown. However, since regional heterogeneity of both contraction and relaxation is well recognised in HCM [9,10] and the presence of dyssynchrony has been shown to be a marker of worse prognosis [11], BiV pacing may be of benefit in this population. The aim of this pilot study was to determine the effect of BiV pacing on symptoms, clinical outcomes and echocardiographic parameters in patients with symptomatic end-stage HCM and LBBB.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusions
 Conflict of interest
 References
 
Patients with HCM, LBBB (QRS duration ≥120 ms) and heart failure symptoms for at least 3 months despite medical therapy (NYHA functional class ≥2) were selected for BiV pacemaker implantation. The diagnosis of HCM was based on the presence of left ventricular hypertrophy greater than 2 standard deviations above expected values in the absence of another cardiac or systemic disease [12]. All patients were followed up regularly in a dedicated cardiomyopathy clinic prior to and following implantation.

2.1. Pre-implant assessment
Clinical history and examination, current medications, 12 lead ECG and the results of 24 hour ambulatory Holter monitoring were recorded. All patients underwent a symptom limited exercise test on an upright bicycle ergometer using a ramp protocol with continuous respiratory gas analysis as previously described [13]. Peak oxygen consumption (VO2 peak) was defined as the mean of the values obtained over the last 20 s of exercise and was expressed as a percentage of the predicted maximum value.

2.2. Echocardiography
All patients underwent M-mode, 2-D and Doppler echocardiographic assessment before device implantation. Standard parasternal and apical views were obtained with the patient in the left lateral position. Left ventricular end-diastolic (LVEDD) and left ventricular end-systolic diameters (LVESD) were assessed from M-mode images in the parasternal long axis views. Ejection fractions were calculated using Simpson's biplane method. Fractional shortening was determined from the formula: ((LVEDD–LVESD)/LVEDD)x100. Left atrial (LA) diameter was measured from the parasternal long axis view. LA volume was calculated using the ellipsoid formula from parasternal and apical views and corrected for body surface area [14].

Tissue Doppler imaging was available before implantation for the latter 14 patients in this series although image quality was insufficient in 3 of these for analysis. Thus in 11 patients, echocardiographic images were analysed retrospectively to assess dyssynchrony. Pulsed-wave Doppler was used to quantify the ventricular pre-ejection periods for both right and left ventricles and the difference used to ascertain inter-ventricular dyssynchrony. Intra-ventricular dyssynchrony was measured using tissue Doppler imaging of the apical 4- and 2-chamber views with images stored digitally for off-line analysis. For each view, a minimum of 3 consecutive cardiac cycles were obtained in held expiration with sector width and depth adjusted to optimize frame rate. Sample volumes were positioned in the basal segments of the septal, lateral, anterior and inferior walls, and the time from QRS onset to peak tissue velocity was calculated. Intra-ventricular dyssynchrony was defined as the maximal difference in time to peak velocity between segments [15]. Patients were considered to have significant dyssynchrony if inter-ventricular dyssynchrony was greater than 40 ms [16] and/or intra-ventricular dyssynchrony was greater than 65 ms [15].

2.3. Device implantation
Device implantation was undertaken in an electrophysiology laboratory using a transvenous approach under local anaesthesia. Commercially available BiV devices (Contak Renewal [Guidant Corp, MN, USA], Atlas HF [St Jude Medical, MN, USA] and In Sync III [Medtronic, MN, USA]), and dedicated coronary sinus guide sheaths and leads were used. BiV implantable cardioverter defibrillators (ICDs) were implanted as indicated on clinical grounds. The right ventricular (RV) lead was positioned in the RV apex and the atrial lead in the right atrial appendage. The LV lead was positioned in a tributary of the coronary sinus, aiming for a lateral or posterolateral branch wherever possible [17].

2.4. Post-implant
Patients were followed up regularly in pacing and cardiomyopathy clinics. Patients with an improvement in NYHA class were classified as responders and those with no improvement or worsening NYHA class as non-responders. All patients underwent follow-up echocardiography using the same protocol to assess changes in cardiac function and dimensions. Devices were interrogated to confirm that outputs were sufficiently above lead thresholds for consistent capture, and that all patients were adequately biventricularly paced. Since the majority of patients were in atrial fibrillation, there was no formal echocardiographic optimisation of the devices and for all patients the AV delay was set at 100 ms and the V-V delay at 0 ms.

2.5. Statistical analysis
Continuous variables are expressed as mean±standard deviation unless otherwise stated. The paired Student's t-test was used to compare data before and after BiV pacing and the unpaired Student's t-test for comparison of baseline characteristics between groups. A p level of <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusions
 Conflict of interest
 References
 
Between 2003 and 2006, 20 HCM patients were selected for implantation of a BiV device for symptoms of heart failure; in all but 4 of these patients, a BiV-ICD was indicated. Three patients were in NYHA functional class II and the remaining 17 were in Class III. One patient had previously undergone atrioventricular nodal ablation with permanent pacemaker insertion for symptomatic atrial fibrillation (AF) and was pacing dependent. Two patients with AF had ICDs in situ and were receiving pharmacologic therapy for rate control such that they were paced from the RV apex at least 90% of the time. Baseline clinical details, echocardiographic measurements and medications are presented in Table 1.


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  		Table 1 Baseline characteristics (n=20)

 
All patients underwent successful percutaneous implantation of an LV lead via the coronary sinus. In one patient phrenic nerve stimulation occurred with the LV lead positioned in all available lateral branches necessitating use of the middle cardiac vein. In the other patients, the final LV lead position was in a true lateral branch in 11, a posterolateral branch in 4 and an anterolateral branch in 4 patients. There were no acute complications relating to the procedures. Two patients required LV lead repositioning at follow-up, the first for phrenic nerve stimulation secondary to lead displacement and the second following the development of exit block.

3.1. Clinical response
The mean follow-up time was 13±6 months. Eight (40%) patients reported an improvement of at least one NYHA functional class (responders). In a further 9 patients there was no change and in 3 patients there was worsening of NYHA class (non-responders). Four patients subsequently underwent cardiac transplantation for symptoms of heart failure (1 responder, 3 non-responders). Two patients (both non-responders) suffered a stroke during the follow-up period. For the cohort as a whole, there was no significant change with BiV pacing in ejection fraction (45±14% vs 46±13%), fractional shortening (25±8% vs 25±8%), LVEDD (54±8 mm vs 53±8 mm), LA diameter (57±10 mm vs 56±7 mm), or indexed LA volume (63±25 cm3/m2 vs 56±19 cm3/m2), p=ns for all comparisons. Fifteen patients (75%) had measurement of peak VO2 after implantation; the remainder (all non-responders) was unable or unwilling to repeat the assessment. Mean percentage predicted peak oxygen consumption decreased from 54±7% to 44±12% (p=0.020).

3.1.1. Responders vs non-responders
There were no significant differences in baseline ejection fraction, fractional shortening, LVEDD, indexed LA volume, maximal wall thickness, percentage predicted peak VO2 or QRS duration between responders and non-responders. Of the three patients with previously implanted devices and more than 90% RV apical pacing, two were responders and one was a non-responder. Of the four patients whose lead was implanted in an anterolateral branch of the coronary sinus, one was a responder and three were non-responders.

In responders, there was a significant increase in ejection fraction (from 41±14% to 50 ±12%, p=0.009), fractional shortening (from 21±8% to 28±8%, p<0.001), and significant reductions in LVEDD (57±6 mm to 52±7 mm, p=0.031), LA diameter (65±8 mm to 57±6 mm, p=0.005) and indexed LA volume (75±28 cm3/m2 to 63±26 cm3/m2, p=0.009) [Fig. 1(a-d)]. For non-responders, ejection fraction decreased from 48±14% before pacing to 43±14% (p=0.048) and fractional shortening worsened from 28±8% before pacing to 23±8% (p=0.006). There were no significant changes in other echocardiographic parameters in non-responders. Percentage expected VO2 peak was unchanged in responders (55±21% vs 50±11%, p=ns) but reduced in non-responders (54±16% vs 37±8%, p=0.029) [Fig. 2]. Mean QRS duration was not reduced by pacing in either group (148±26 ms vs 143±24 ms, p=ns for responders; 156±18 ms vs 156±26 ms, p=ns for non-responders).


Figure 01
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  		Fig. 1 Echocardiographic parameters before (Pre) and after (BiV) biventricular pacing in responders and non-responders. Linked points represent data for individual patients. Large circles represent mean values, vertical lines standard deviations. The number of patients for whom data was available is given. a) Fractional shortening, %; b) LV end-diastolic diameter (LVEDD), mm; c) LA diameter (LAD), mm; d) indexed LA volume (LAVi), cm3/m2. NS = Not significant.

 


Figure 02
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  		Fig. 2 Percent predicted peak oxygen consumption (peak VO2) before (Pre) and after (BiV) biventricular pacing in responders and non-responders. Linked points represent data for individual patients. Large circles represent mean values, vertical lines standard deviations. The number of patients for whom data was available is given.

 
3.2. Atrial fibrillation burden
Seventeen patients had a history of atrial arrhythmias before BiV device implantation. Those who had undergone at least one successful cardioversion of AF in the 12 months leading up to implant with maintenance of sinus rhythm for more than 24 h were classified as persistent AF. Patients in whom cardioversion had been unsuccessful or who had previous AV nodal ablation for AF were classified as permanent AF. Patients with documented self-terminating paroxysms of AF on Holter monitoring in the 12 months before implant were classified as paroxysmal AF. The remainder was classified as sinus rhythm based on 12 lead ECGs and Holter monitors performed in the 12 months before implant. Following implantation, devices were interrogated to determine mode-switching episodes, intra-cardiac electrograms and atrial arrhythmia burden. AF classes for all patients before and after implantation are compared in Fig. 3. Among responders, 5 patients had a reduction in AF burden including one patient, who had previously required cardioversions, maintained in sinus rhythm throughout follow-up. In contrast, in the non-responder group, 4 patients experienced worsening of AF burden and no patients improved.


Figure 03
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  		Fig. 3 Atrial fibrillation (AF) burden of patients before (Pre) and after (BiV) biventricular pacing. See text for explanation of AF classification. The number of patients in each class is given in the boxes. Responders and non-responders are presented separately.

 
3.3. Echocardiographic assessment of dyssynchrony
Of the 11 patients who had pre-implant tissue Doppler imaging data available for assessment of mechanical synchrony, 6 met the criteria for dyssynchrony described above. Of these 6 patients, 4 clinically responded and 2 were non-responders. The remaining 5 patients did not meet the thresholds for dyssynchrony; 1 was a responder and 4 were non-responders.


   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusions
 Conflict of interest
 References
 
This short term pilot study demonstrates that BiV pacing is a useful treatment option for heart failure symptoms in some patients with end-stage HCM. In addition, symptomatic improvement was associated with reverse remodelling of the LV and echocardiographic evidence of improved systolic function, paralleling the results of trials of BiV pacing [7,18,19]. In contrast to non-responders, patients who experienced an improvement in symptoms had no deterioration in exercise capacity during follow-up, suggesting that BiV pacing may have stabilized disease progression. Finally, despite the relatively small numbers of patients in the study, there was a high rate of major clinical events in the non-responders (3 cardiac transplants and 2 strokes) compared to responders (1 transplant, no strokes).

4.1. Mechanism of symptomatic improvement
A number of studies in heart failure patients with LBBB have shown that BiV pacing improves exercise capacity, quality of life, and substantially reduces hospitalisation [6-8]. However, the mechanism of improvement is not fully understood and approximately 30% of patients do not respond to BiV pacing [6,8]. It is postulated that improvement in mechanical function is related to a reduction in inter- or intra-ventricular dyssynchrony [19,20] and a number of authors have attempted to identify echocardiographic parameters that predict response to BiV pacing [16]. In this study, clinical response (or non-response) would have been correctly predicted in 8 out of the 11 patients who underwent echocardiographic assessment of systolic dyssynchrony. Further extrapolation of published trials of BiV pacing to the HCM population must be limited by the important differences between the population of this study and those enrolled in the major trials of BiV pacing, particularly baseline ejection fraction and ventricular dimensions. Nonetheless, numerous studies have shown that HCM is characterized by marked regional heterogeneity of myocardial contraction and relaxation caused by the patchy distribution of myocardial hypertrophy, myocyte disarray and fibrosis [9,10,21,22]. In two studies, improvements in global relaxation and filling with verapamil were attributed to a reduction in diastolic dyssynchrony [21,22] and it is possible that a reduction in myocardial dyssynchrony also explains the beneficial effects of BiV pacing observed in this study.

Some of the acute haemodynamic benefit of BiV pacing may be explained by a reduction in external constraint to LV filling by the pericardium and RV, a phenomenon known as diastolic ventricular interaction (DVI) [23]. Many patients with HCM have raised LV and RV end-diastolic pressures (EDP) at rest which can increase dramatically during exercise [24]. Based on observations in patients with heart failure, DVI might be anticipated to be present at rest or to develop during exercise in such patients. If this is so, then the effective distending pressure in the LV might not increase in spite of an increase in LVEDP during exercise, resulting in an impaired stroke volume response during exercise [23]. By altering the relative timing of left and right ventricular filling, BiV pacing might have reduced DVI and thus improved stroke volume and LV filling pressures [25].

A further factor in the improvement may have been the restoration (and maintenance) of sinus rhythm. Many of the responders in this study were in persistent AF before pacing, but following BiV pacing the majority had a reduction in AF burden with one patient successfully maintained in sinus rhythm. Since LA stretch is known to increase susceptibility to AF [26], this improvement very likely relates to the decrease in LA dimensions observed in responders. While the reduction in AF burden almost certainly contributed to the improvement in NYHA class seen in responders, it seems likely it was the consequence and not the cause of a reduction in LV filling pressure, a conclusion supported by the significant improvements in LV and LA dimensions in responders.

4.2. Clinical implications
BiV pacing is recommended for the treatment of heart failure in patients with reduced ejection fraction and electrocardiographic evidence of conduction delay [27]. This pilot study (and two recent case reports [28,29]) suggests that implantation of a BiV device is a useful adjunct to conventional heart failure therapy in patients with end-stage HCM. As both LA dilatation [30] and the presence of mechanical dyssynchrony [11] have been shown to be associated with a worse prognosis in HCM, the significant improvements in ventricular and atrial dimensions seen in this study may confer important prognostic advantages including a reduction in stroke risk. However, the proportion of responders in this study was lower than in published series of BiV pacing and larger, prospective trials are required to determine whether particular characteristics can be used to identify which HCM patients are more likely to respond.

4.3. Limitations
Since this is an observational study of a small number of patients who were implanted over a period of several years there are several important limitations. Firstly, assessment of heart failure status was determined by a clinician using the NYHA classification rather than patient self-assessment. A more formalised assessment of symptoms (e.g. with the Minnesota Living with Heart Failure Questionnaire) would be preferable and this should be addressed in future trials. Secondly, the echocardiographic studies were performed by several different operators and it is possible that inter-operator variability could have contributed to the improvements seen in echo parameters. Thirdly, only 11 patients had tissue Doppler data available for analysis as this was not routinely obtained during echo studies in the early part of the study. Fourthly, due to the high proportion of patients in AF there are insufficient data to comment on echocardiographic parameters of diastolic function in this cohort. Finally, there was relatively low use of angiotensin converting enzyme inhibitors and beta blockers compared to comparative heart failure trials reflecting, in part, poor tolerance of many of these agents in patients with end-stage HCM.


   5. Conclusions
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
Conflict of interest
 References
 
Therapeutic options are currently limited in patients with end-stage HCM. This study suggests that BiV pacing may be useful in a subset of these patients with QRS prolongation. Reduction of LV and LA dimensions, a decrease in AF burden and improvement of dyssynchrony may also confer prognostic benefits. The indications for this therapy and its applicability to a wider HCM population need to be addressed in a formal prospective clinical trial.


   Conflict of interest
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Conflict of interest
References
 


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   References
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusions
 Conflict of interest
 References
 
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