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European Journal of Heart Failure 2009 11(1):53-57; doi:10.1093/eurjhf/hfn016
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Published on behalf of the European Society of Cardiology. All rights reserved. © The Author 2009. For permissions please email: journals.permissions@oxfordjournals.org.

Heart rate per se impacts cardiac function in patients with systolic heart failure and pacing: a pilot study

Damien Logeart1,2,*, Jean-Pierre Gueffet3, François Rouzet4, Françoise Pousset5, Christophe Chavelas1, Alain Cohen Solal1,2,6 and Guillaume Jondeau6,7

1 Hôpital Lariboisière, Cardiology Department, Assistance Publique – Hôpitaux de Paris, Paris, France
2 INSERM U942, Paris, France
3 Centre Hospitalo-Universitaire Hotel-Dieu, Cardiology Department, Nantes, France
4 Groupe Hospitalier Bichat – Claude Bernard, Nuclear Medicine Department, Assistance Publique – Hôpitaux de Paris, France
5 Groupe Hospitalier Pitié Salpétrière, Cardiology Department, Assistance Publique - Hôpitaux de Paris, Paris, France
6 University Paris Diderot, Paris, France
7 Groupe Hospitalier Bichat – Claude Bernard, Cardiology Department, Paris, France

* Corresponding author. Cardiology Department, Lariboisière Hospital, 2 rue Ambroise Paré, 75010 Paris. Tel: +33 149956608, Fax: +33 149958439, Email: damien.logeart{at}lrb.aphp.fr.


   Abstract
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 Abstract
Introduction
 Methods
 Results
 Discussion
 Funding
 References
 
Aims: This study was designed to compare the specific effects of two heart rates (HR), 55 and 75 b.p.m., in patients with heart failure (HF).

Methods and results: Patients with chronic HF, left ventricular ejection fraction (LVEF) ≤ 35%, and a pacemaker with >90% of paced QRS, were included in a randomized cross-over trial of two 3-month periods where pacing rate was set at either 55 or 75 b.p.m. At the end of each period, patients were examined and radionuclide ventriculography, echocardiography, and blood sampling were performed for centralized and blinded analysis. Two patients did not complete the study because of early worsening while paced at 75 b.p.m. Twelve patients completed the study. Compared with 75 b.p.m., pacing at 55 b.p.m. was associated with a higher LVEF [+4.7% (2.6–6.7), P < 0.001], lower B-type natriuretic peptide levels [–91 pg/mL (–148 to –33), P < 0.01], lower systolic pulmonary artery pressure (41 ± 10 vs. 47 ± 10 mmHg, P = 0.02) and lower NYHA (New York Heart Association) class (2.2 ± 0.6 vs. 2.6 ± 0.5, P = 0.03). The baseline pacing rate prior to inclusion had no effect on results.

Conclusion: HR per se may impact cardiac function and low HR might be beneficial in patients with systolic HF compared with intermediate HR.

Key Words: Heart rate • Pacing • Heart failure • Ventricular function

Received April 20, 2008; Revised September 11, 2008; Accepted November 3, 2008


   Introduction
Top
 Abstract
 Introduction
Methods
 Results
 Discussion
 Funding
 References
 
There is an increasing interest in the specific role of heart rate (HR) in a number of cardiovascular diseases including hypertension, atherosclerosis, myocardial infarction, and heart failure (HF).1 HR is usually increased in chronic HF and correlates positively with mortality.2,3 It has been speculated that HR lowering is beneficial by possibly increasing left ventricular (LV) filling, preventing LV ischaemia (by increasing the time for diastolic coronary perfusion as well as decreasing myocardial oxygen consumption), and altering ventriculo-arterial coupling.1,4 However, the precise role of HR in the pathophysiology of HF is poorly understood. Furthermore, HR reduction-related decrease in cardiac output can be harmful and not necessarily offset by the previously mentioned effects. Mechanisms of benefit obtained with beta-blocker therapy in HF remain unclear; some analyses suggest that the effects of beta-blockade bear little relation to the degree of HR reduction.2,5 One experimental study in HF has demonstrated that HR reduction could be responsible for a significant part of the positive beta-blocker-related effects.6 Experimental studies using If channel blockers, which have pure bradycardic effects, have shown different results according to the HF model used.7–10 Finally, the clinical effects of long-term HR altering per se on HF are unknown.

Patients who are dependant on a cardiac pacemaker provide the possibility of testing the effects of HR per se without altering any other parameter. In addition, the optimal pacing rate in patients with systolic HF is unknown and current guidelines provide no specific recommendation. In the present study, we analysed the effects of two pacing HRs—55 and 75 beats per minute (b.p.m.)—using a cross-over design over 5-month periods.


   Methods
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 Abstract
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 Methods
Results
 Discussion
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 References
 
Patients
The eligibility criteria were as follows: HF, New York Heart Association (NYHA) class 2 or 3, LV ejection fraction (LVEF) ≤ 35%, no change in medications for >3 months (except diuretics), pacing for >3 months and evidence of dependence on pacing by pacemaker telemetry (>90% of paced beats). Exclusion criteria were: severe valvular heart disease, hypertrophic cardiomyopathy, decompensated HF or unplanned hospitalization during the previous month, evidence of myocardial ischaemia, severe ventricular arrhythmia, or alcohol abuse. Written informed consent was obtained from all patients and the study protocol was approved by an independent research ethics committee (Saint Antoine Hospital, Paris).

Study design
This was a two 3-month period randomized cross-over study which was conducted under the auspices of the Heart Failure Working Group of the French Society of Cardiology. Firstly, patients were randomly assigned into two groups to be paced at a rate of either 55 or 75 b.p.m. for 3 months. At the end of the first 3-month period an assessment of endpoints was performed; then the patients had their pacemaker rate switched from one rate to the other for the second 3-month period, after which time they underwent a second assessment. When patients were paced with a rate responsive algorithm, the upper limit was set in order to maintain a difference of 20 b.p.m. between the two pacing rates. The number of paced beats as a percentage of the total was derived from both Holter-ECG and pacemaker telemetry: 24 h Holter-ECG was recorded after each one of the changes in pacing rate and internal pacemaker histograms were obtained from telemetry at the end of each 3-month period. Dependence on the pacemaker was established by >90% of beats paced. At the end of the study, the pacing rate was set at the rate that the physician and/or patient preferred.

Endpoints
The effects of each pacing rate were assessed by the following parameters:

  • The primary endpoint was the LVEF which was measured using gated blood-pool SPECT. Both scans for any one patient were recorded using the same apparatus and the same protocol. Central analysis was performed by a blinded investigator.
  • Blood levels of B-type natriuretic peptide (BNP) were measured from blood samples by the Triage method (Biosite, CA, USA). The normal reference values were <8–63 pg/mL; the coefficient of variation within a given assay were 9, 12, and 14% for levels of 29, 584, and 1180 pg/mL, respectively, and were 10, 12 and 15% among assays.
  • The echographic examination included TM mode-derived LV diameters, pulsed Doppler-derived cardiac output, pulsed Doppler velocities of mitral E-wave (E), Doppler tissular imaging-derived velocity of mitral annulus (Ea), E/Ea ratio, Doppler velocity of tricuspid regurgitation as well as the presence and severity of mitral regurgitation. Both echographic examinations for each patient were performed using the same apparatus and recorded for central and blinded analysis.
  • Clinical assessment included NYHA classification and physical examination. Patients also underwent an electrocardiogram and blood tests to analyse renal function. At the end of the study, patients were asked to report during which period they felt the best.
  • The number of significant ventricular arrhythmias was quantified using both Holter-ECG and pacemaker telemetry. A significant ventricular arrhythmia was defined by at least three consecutive ventricular extrasystoles.

Statistical analysis
Data are reported as mean ± 1SD, or as percentage. The impact of pacing rate on the previously mentioned endpoints was assessed using a mixed-effect linear model, in which pacing rate and baseline paced rate were considered as fixed-effects whereas patient effects were considered as random.11 The analysis was done using Stata 10 for Windows. A P-value of <0.05 was considered as significant.


   Results
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 Abstract
 Introduction
 Methods
 Results
Discussion
 Funding
 References
 
We enrolled 17 patients who met the eligibility criteria. Two patients were excluded from the final analysis because the percentage of paced beats was <85% at the lowest pacing rate. Two others were excluded because of early worsening and subsequent unplanned hospitalization at the highest pacing rate. One patient exhibited severe amiodarone-related hyperthyroidism before completing the study and was also excluded. Therefore, 12 patients completed the study and were available for analysis. Table 1 summarizes their main baseline characteristics. Treatment included ACE (angiotensin-converting enzyme) inhibitors and beta-blockers in all patients with no change in dose for >3 months. The pacing mode was VVI in two patients, DDD in two patients and biventricular pacing in eight patients. Two patients also had an automatic defibrillator for primary prevention of sudden death. Patients were paced for 19 ± 11 (range 6–46) months before randomization. A rate responsive algorithm was set in eight of the patients. The percentages of atrial and ventricular pacing were 93 ± 7 and 98 ± 5%, respectively at the low pacing rate, and 98 ± 5% and 99 ± 3% respectively at the high pacing rate. The atrioventricular delay was 132 ± 28 ms at the low pacing rate and was 130 ± 30 ms at the high pacing rate; only three patients were paced with a dynamic atrioventricular delay.


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  		Table 1 Baseline characteristics of the 12 patients who completed the study

 
The low pacing rate resulted in a significant increase in LVEF (Figure 1) as well as a significant decrease in BNP levels (Figure 2) compared with the high rate. Importantly, the LVEF never decreased at the low pacing rate and only two patients had an increase in BNP levels at the low pacing rate when compared with the high rate. No significant change was observed in the echocardiographic parameters, except for systolic pulmonary artery pressure which was lower at the lowest pacing rate (Table 2). The mean NYHA class was lower at the low pacing rate compared with the high (2.2 ± 0.6 vs. 2.6 ± 0.5, P-value 0.03): it was higher by one class in four patients at the low pacing rate and no patients had a higher class in the higher pacing rate (Figure 3). At the end of the study, seven patients reported no difference between the two pacing periods, four felt better at the low pacing rate and one felt better at the high pacing rate (Figure 3). According to Holter-ECG recordings as well as pace-maker telemetry, there was no difference in the rate of significant ventricular arrhythmia between the two periods. The baseline paced HR as well as the pacing mode had no effect on any of these parameters. In addition, results were similar whether the patient started with the low pacing rate (n = 5) or the high pacing rate (n = 7).


Figure 1
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  		Figure 1 Left ventricular ejection fraction (LVEF) at the end of the two 3-month periods, according to the tested pacing rate. Box-plots show median, 50th and 75th percentiles.

 


Figure 2
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  		Figure 2 Blood B-type natriuretic peptide (BNP) levels at the end of the two 3-month periods, according to the tested pacing rate. Box-plots show median, 50th and 75th percentiles.

 


Figure 3
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  		Figure 3 Left panel: New York Heart Association (NYHA) class at the end of the two 3-month periods, according to the tested pacing rate. The number of patients in each NYHA class is indicated at the end of each period. Lines indicate changes in NYHA class for each patient. Right panel: self-reporting of patients at the end of the study about when they felt the best in the two periods.

 


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  		Table 2 Systolic blood pressure and echographic results at the end of the two 3-month periods

 

   Discussion
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 Abstract
 Introduction
 Methods
 Results
 Discussion
Funding
 References
 
This study indicates that a low HR per se improves LV function as well as clinical status in patients with moderate systolic HF.

Because of the small size of our sample, it was not expected that hard clinical endpoint could be used (two worsening of HF during the 75 b.p.m. period vs. none during the 55 b.p.m. period). However, the cross-over and randomized design as well as very homogeneous positive effects in most patients and on most endpoints give value to our results. In addition, most of the endpoints were measured by blinded investigators. Recent evidence suggests that BNP testing is a valuable surrogate clinical endpoint.12,13 It should be noted that the mean decrease in BNP levels observed in our study is quite striking when compared with clinical trials with BNP testing as an intermediate endpoint.14,15 Interestingly, the low pacing rate resulted in a significant increase in LVEF without significant LV dilation and was also associated with a significant decrease in both BNP levels and pulmonary artery pressure, and a decrease in E/Ea ratio close to statistical significance. Because the systolic blood pressure was slightly increased at the low pacing rate, compared with the high pacing rate, our results suggest an increase in LV contractility at the end of the low pacing rate rather than a decrease in afterload. Such increase in LV contractility could be due to the increase in diastolic LV filling at the low pacing rate, according to Starling’s law, but echocardiographic examinations showed only slight and non significant LV dilation at the low pacing rate compared with the high rate. Alternatively, HR reduction has been shown to improve ventriculo-arterial coupling, in part by decreasing arterial elastance.16,17 Some improvement in LV remodelling could also be considered. Interestingly, Mulder et al.8 demonstrated in experimental systolic HF that HR lowering improved both systolic LV function and myocardial structure; indeed, long-term HR lowering was associated with decreased collagen density and increased capillary density. Another potential mechanism of positive effects of low HR could be the decrease in myocardial O2 consumption because the HR is a major determinant of myocardial O2 consumption.18 Clinical assessment of our patients as well as self-reporting also supported the low pacing rate. Furthermore, two patients were excluded from the final analysis because of severe clinical worsening with unplanned hospitalization occurring during the high pacing rate.

Two recent clinical studies have also analysed the effects of different pacing rates in pacemaker-dependent patients with HF.19,20 By randomizing two groups of patients to either 60 or 80 b.p.m., Thackray et al.19 observed an increase in LV volumes as well as a decrease in LVEF in patients with the highest pacing rate. Because the mean paced rate at entry was 61 b.p.m., the conclusion was that the increase in HR was deleterious. Rao et al.20 tested three pacing rates (60, 75 and 90 b.p.m.) in a cross-over study with three 2-month periods. Again, the pacing rate at entry was 60 b.p.m. and the main result was a deleterious effect on LVEF as well as functional capacity at the highest pacing rate—90 b.p.m.—which is not within physiological ranges. In this last study, there was no significant difference between the two other pacing rates of 60 and 75 b.p.m. Thus, the results of these two studies show that the increase in HR is deleterious in patients with HF and the authors conclude that the pacemaker-related increase in HR from 60 to 80 or 90 b.p.m. reverses the positive effects of beta-blockers, at least in part. Our study gives the first clinical evidence of beneficial effects of low HR per se in patients with HF. Firstly, the high pacing rate we tested—75 b.p.m.—is in fact an ‘intermediate’ rate, i.e. a physiological rate, close to the mean HR which is usually observed in HF surveys when patients are treated with beta-blockers.21,22 Secondly, the low pacing rate we tested—55 b.p.m.—really is a low rate, significantly lower than the mean baseline-paced rate of our patients in clinical practice.

There is a current lack of guidelines about pacing rate for patients with permanent pacing: the rate is usually set according to local practice of the rhythmologist. Our results, as well as those of the two other studies discussed previously, are thus of interest in this setting and suggest that a low, or relatively low, pacing rate could be set in pacemaker-dependent patients with stable HF.

Some limitations nevertheless deserve to be discussed. Firstly, our results cannot be extended to all types of HF. As an example, a low pacing rate could be harmful in patients with severe or decompensated HF as well as in patients with severe diastolic dysfunction. Secondly, because most of our patients were paced with biventricular pacing (during the two pacing periods), specific effects of ventricular resynchronization according to different pacing rates cannot be excluded.

In conclusion, our results suggest that HR per se may impact on cardiac function and clinical status in patients with stable systolic HF. Low HR might be beneficial in such patients compared with intermediate or relatively high HR. Ongoing trials with If channel blockers should further define the relevance of such a therapeutic strategy.

Conflict of interest: G.J. and A.C.S. declare having received fees from Medtronic and Guidant.


   Funding
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
References
 
This work was supported by grants from the Fondation de France (Paris, France).


   References
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 Funding
 References
 

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