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European Journal of Heart Failure 2003 5(2):175-178; doi:10.1016/S1388-9842(02)00257-X
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© 2002 European Society of Cardiology

Effect of biventricular pacing on heart rate variability in patients with chronic heart failure

Efthimios G. Livanis*, Panagiota Flevari, George N. Theodorakis, Fotis Kolokathis, Dionyssios Leftheriotis and Dimitrios Th. Kremastinos

Second Department of Cardiology, Onassis Cardiac Surgery Center 356 Syngrou Avenue, 17674 Athens, Greece

* Corresponding author. Tel.: +30-10-9493-372; fax: +30-10-9493-373 E-mail address: elbee{at}ath.forthnet.gr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: Biventricular pacing is emerging as a long-term therapy for symptomatic heart failure. Analysis of heart rate variability (HRV) has become an important predictive tool in this syndrome.

Aim of the study: To assess whether chronic resynchronization therapy can affect HRV in patients with heart failure.

Methods and results: Thirteen patients with heart failure were studied (mean age±1 S.E. 65±2.2 years, QRS 195±5.3 ms, NYHA class 3.2±0.1, LVEF 21±1.7%). The protocol included a preliminary no pacing period for 1 month following device implantation. Twenty-four hour Holter ECG recordings were performed at the end of this period (baseline) and after 3 months of biventricular stimulation (VDD mode). Prior to and following pacing patients underwent NYHA class evaluation, 6-min walk test, Quality of Life Assessment and a cardiopulmonary exercise test. Biventricular pacing improved functional class (P<0.0001) and Quality of life (P<0.0001), increased 6-min walk distance, (P=0.008) and exercise duration (P<0.0001) but had no significant effect on peak exercise VO2. Resynchronization therapy increased mean 24-h RR (922±58 vs. 809±41 ms at baseline, P=0.006), SDNN (111±11 vs. 83±8 ms, P=0.003), SDNN-I (56±10 vs. 40±5 ms, P=0.02), rMSSD (66±14 vs. 41±8 ms, P=0.003), Total Power (5724±1875 vs. 2074±553 ms2, P=0.03), Ultra Low Frequency Power (1969±789 vs. 653±405 ms2, P=0.03) and Very Low Frequency Power (2407±561 vs. 902±155 ms2, P=0.004).

Conclusion: Biventricular pacing in heart failure improves autonomic function by increasing HRV. This may have important prognostic implications.

Key Words: Biventricular pacing • Heart rate variability • Heart failure

Received August 2, 2002; Revised October 18, 2002; Accepted December 5, 2002


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
Biventricular pacing is emerging as a long-term therapy for symptomatic heart failure in patients with intraventricular conduction disturbances [1–3]. Analysis of heart rate variability (HRV) has become an important method for assessing cardiac autonomic regulation and has been shown to predict clinical outcome in heart failure [4,5]. The aim of the present study was to assess whether chronic resynchronization therapy can affect HRV.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
The study group consisted of 13 consecutive patients with symptomatic heart failure (New York Heart Association III–IV) and ventricular conduction delay (baseline QRS duration, mean±1 S.E.: 195±5.3 ms), mean aged 65±2.2 years, mean ejection fraction 21±1.7% (range 14–37), on optimal medical therapy. All patients were successfully implanted a biventricular pacemaker with (n=10) or without (n=3) additional defibrillator therapy. Defibrillators were implanted according to the ACC/AHA guidelines [6]. Heart failure of these patients was due either to coronary artery disease (n=7) or idiopathic dilated cardiomyopathy (n=6). The present investigation conforms with the principles outlined in the Declaration of Helsinki. For at least 1 month before baseline HRV evaluation all subjects received ongoing drug therapy at unchanged doses; medications were not changed during follow-up and patients were advised to avoid body weight changes during the study. The protocol included a preliminary no pacing treatment period for 1 month following implantation. Twenty-four hour Holter ECG recordings were performed at the end of the month without pacing (baseline) and after 3 months of biventricular stimulation (VDD mode). All patients underwent 24-h Holter monitoring using a 3-channel tape recorder (Oxford, MR-4500-3). Recordings were analyzed by 2 independent observers. The Oxford Holter System (Medilog, Excel-2, Version 7.1, Oxford Instruments, Abingdon, Oxon, UK) was used for tape analysis. Artifacts, premature beats and postextrasystolic pauses were excluded from further analysis. In one case of poor-quality Holter recording, the patient underwent a second 24-h recording on the following day. All tapes were subsequently analyzed to measure HRV. The following time domain measurements of HRV were calculated from 24-h electrocardiographic recordings: S.D. of all normal RR intervals, S.D. of 5-min mean RR intervals, mean of all 5-min S.D. of RR intervals (SDNN-I), root-mean-square difference of successive RR intervals (rMSSD), and percentage of adjacent normal RR intervals differing by >50 ms (pNN50). Power spectral analysis of the RR interval signal was performed by an autoregressive mode, which provides two separate peaks: a high-frequency peak related to respiration and a low-frequency peak unrelated to any respiratory event. We evaluated the power of the harmonic components in the range 0.00–0.40 Hz (Total Power), 0.00–0.0033 Hz (Ultra Low Frequency), 0.0033–0.04 Hz (Very Low Frequency), 0.04–0.15 Hz (Low Frequency) and those in the range 0.15–0.40 Hz (High Frequency component). The difference between operators for HRV measurements was <5%. Intraobserver variability was again <5%. Prior to and following pacing therapy, all patients underwent clinical examination, functional capacity evaluation (NYHA class), an echocardiogram, 6-min walk test [7], Quality of Life Assessment (Minnesota questionnaire) [8] as well as a cardiopulmonary exercise test. This was conducted by the Dargie treadmill protocol. Respiratory gas analysis was performed with a Medical Graphics system (Medical Graphics Corporation, St. Paul, MN). The anaerobic threshold was calculated by the standard V slope method (VO2 at which expired carbon dioxide production increased nonlinearly relative to VO2). The peak exercise VO2 value was defined as the highest VO2 value achieved at end-exercise after the anaerobic threshold was reached. Results are presented as mean±1 S.E. ANOVA was used for statistical evaluation. A P value <0.05 was considered statistically significant.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
As shown in Table 1, 3 months of biventricular pacing improved study patients’ functional class (P<0.0001) and Quality of life (P<0.0001), increased 6-min walk test distance, (P=0.008) and exercise duration (P<0.0001) but had no significant effect on peak exercise VO2. Echocardiographic left ventricular ejection fraction showed a non-significant increase (P=0.06). Resynchronization therapy increased mean 24-h RR (922±58 vs. 809±41 ms at baseline, P=0.006), SDNN (111±11 vs. 83±8 ms, P=0.003), SDNN-I (56±10 vs. 40±5 ms, P=0.02), rMSSD (66±14 vs. 41±8 ms, P=0.003), Total Power (5724±1875 vs. 2074±553 ms2, P=0.03), Ultra Low Frequency (1969±789 vs. 653±405 ms2, P=0.03) and Very Low Frequency (2407±561 vs. 902±155 ms2, P=0.004). Changes of HRV parameters showing significant improvement are shown schematically in Fig. 1. A significant correlation was observed between the % change in left ventricular end-systolic diameter and the % difference in the Very Low Frequency Power of HRV (r=–0.88, P=0.002).


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  		Table 1 Characteristics of study patients at baseline and following 3 months of biventricular pacing

 


Figure 1
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  		Fig. 1 Changes of HRV parameters showing significant improvement by biventricular pacing.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
Chronic cardiac resynchronization therapy may achieve several of the treatment goals in heart failure, including symptom reduction and slowing of heart failure progression [2], while its impact on survival is currently under consideration by prospective, randomized trials [3].

In the present study, for the first time to our knowledge, an increase has been shown in several HRV indexes of patients with heart failure functionally improved by chronic resynchronization therapy. The reduction in HRV indexes observed in heart failure has been interpreted as being the result of a shift of autonomic balance towards sympathetic predominance [9,10]. Our finding of increases in mainly sympathetic HRV indexes following biventricular pacing is compatible with the recently reported decrease in sympathetic nervous system activation observed following biventricular pacing [11]. The importance of such a finding is related to the fact that decreased HRV provides important prognostic information on patients with heart failure regarding arrhythmic as well as nonarrhythmic mortality [4,5,12,13]. Therefore, it could be postulated that an increase in HRV, as presently observed, might be related to a possible decrease in mortality of patients with heart failure who undergo ventricular resynchronization therapy. As an indicator of tonic autonomic outflow, HRV improvement may also be related to the recently reported protection against arrhythmias exerted by biventricular pacing in patients with heart failure [14,15].

The fact that a traditionally accepted marker of mainly sympathetic activity, Low Frequency Power, did not show significant improvement in our patient group may be related to the previously reported technical problems of spectral methods of HRV analysis [16] and/or the inability of Low Frequency Power to constitute a marker of the mean level of the increased sympathetic drive observed in heart failure. As it is known [17], in the more severe stages of the disease, the neurohormonal excitation reduces reflex modulation of heart rate to such an extent that above 0.03 Hz only small fluctuations that are synchronous with breathing activity are detectable.

It is worth noting that in our patient population peak VO2 values did not change following biventricular pacing, despite the fact that functional capacity, 6-min walk as well as exercise tolerance were improved. Our finding of no significant increase in peak VO2 is in keeping with the results of a recent study assessing this parameter in patients with heart failure receiving biventricular pacing. As reported [18], patients without a particularly reduced peak VO2 did not receive significant benefit. In addition, the usefulness of intermediate values of peak exercise VO2 as prognostic indicators in heart failure has recently been reconsidered [19,20]. It is possible that improvement in peak VO2 might have been of statistical significance if more patients had been included in the study, as observed in larger-scale trials [3], or if patients with particularly reduced peak VO2 had been studied [18]. In patients with heart failure similar to those presently studied, HRV indexes may be more sensitive markers of functional improvement than peak VO2 and this may be useful for prognostic stratification.

In conclusion, in patients with heart failure and ventricular conduction disturbances, biventricular pacing improves HRV indexes. This finding confirms that biventricular pacing exerts a positive effect on the mechanisms that sustain the harmful hyperadrenergic state and affect prognosis.


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

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