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European Journal of Heart Failure 2004 6(2):181-185; doi:10.1016/j.ejheart.2003.09.007
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© 2003 European Society of Cardiology

Heart rate variability in severe right or left heart failure: the role of pulmonary hypertension and resistances

Laurent Fauchier*, Dominique Babuty, Alexandre Melin, Pierre Bonnet, Pierre Cosnay and Jean Paul Fauchier

Service de Cardiologie B et Laboratoire d’Électrophysiologie Cardiaque Centre Hospitalier Universitaire Trousseau, Tours, France

* Corresponding author. Tel.: +33-2-47-47-46-50; fax: +33-2-47-47-59-19. E-mail address: lfau{at}med.univ-tours.fr


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Background: The decrease in heart rate variability (HRV) might be related to the hemodynamic status in heart failure. However, HRV in patients with severe isolated right heart failure has not been extensively studied.

Aims: This study compared HRV in patients with congestive heart failure (CHF) and in patients with isolated right heart failure.

Methods: Time and frequency domain analysis of HRV on 24-h ECG recording was assessed in 15 healthy subjects and in two groups of patients with severe heart failure awaiting heart or heart/lung transplantation. These were 15 patients with CHF due to idiopathic dilated cardiomyopathy (IDC) and 10 patients with isolated right heart failure due to primary pulmonary hypertension (PPH).

Results: Measurement of HRV were significantly decreased in both groups of patients compared with the control group. Patients with IDC had higher pulmonary capillary wedge pressure than patients with PPH (P=0.04) but lower pulmonary artery pressure and lower pulmonary vascular resistance (PVR) (P<0.0001). However, all the measurements of HRV were significantly lower in patients with IDC than in patients with PPH (range 22–77%, P<0.05 to P<0.01). None of the HRV measurements correlated with filling pressure measurements.

Conclusions: The increase in pulmonary vascular resistance in heart failure is not the main causal factor behind a decrease in HRV.

Key Words: Heart rate variability • Heart failure • Pulmonary hypertension

Received November 1, 2002; Revised May 29, 2003; Accepted September 15, 2003


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 5. Conclusion
 References
 
Imbalanced regulation of the cardiac autonomic nervous system is one of the important pathophysiological changes in congestive heart failure; analysis of heart rate variability (HRV) provides information about these disturbances. Previous studies have shown that HRV was decreased and could predict cardiac events in patients with congestive heart failure (CHF) [1–4]. Moreover, it has been suggested that the decrease in HRV was related to the severity of the hemodynamic status in CHF [1,3,5,6]. However, the characteristics of HRV in patients with severe isolated right heart failure have not been extensively studied. The aim of this study was to compare the characteristics of HRV in congestive heart failure and in isolated right heart failure.


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 5. Conclusion
 References
 
2.1. Patients
This was an observational study. Patients received information about their clinical status and gave oral consent for the several investigations that were needed and then reviewed for the present study. The investigation therefore conformed with the principles outlined in the Declaration of Helsinki. Two groups of patients with severe heart failure awaiting heart or heart/lung transplantation were studied. Patients with chronic renal failure, diabetes mellitus, atrial arrhythmias, sinus node dysfunction, atrioventricular block or with a permanent pacemaker were excluded for analysis of HRV.

The first group consisted of 15 patients (10 men, aged: 38±11 years) with idiopathic dilated cardiomyopathy (IDC) according to the definition of the World Health Organization [7]. Diagnosis was established by normal coronary angiography, echocardiography, and radionuclide-gated blood pool ventriculography. At the time of the 24-h ambulatory electrocardiographic (ECG) recording, all the patients were being treated with diuretics, digoxin, and angiotensin-converting enzyme (ACE) inhibitors.

The second group consisted of 10 patients with isolated right heart failure due to primary pulmonary hypertension (PPH) (five men, aged: 35±15 years). The diagnosis of PPH was defined according to the criteria of the National Institutes of Health Patient Registry for the Characterization of PPH [8]. Secondary causes of pulmonary hypertension were excluded based on the results of clinical and laboratory examination, chest radiography, pulmonary function testing, echocardiography, perfusion lung scan and/or pulmonary angiography and coronary angiography. At the time of the 24-h ambulatory ECG recording, all the patients were being treated with diltiazem (n=7) or verapamil (n=3).

The two groups of patients had severely compromised hemodynamic status, despite medical treatment, as reflected by exertional symptoms, markedly decreased exercise tolerance and/or decreased cardiac index or pulmonary artery resistance. They were all awaiting either heart transplantation, for patients with IDC, or heart/lung transplantation, for patients with PPH.

The control group included 15 healthy subjects aged 20–60 years (eight men, age: 36±13) with no cardiovascular symptoms, a normal general examination, no medication that might affect autonomic nervous activity, normal ECG, normal echocardiography and coronary angiography in subjects aged >50 years. They had a limited activity during the 24-h ambulatory ECG recording.

2.2. Twenty-four-hour ambulatory ECG recording
A 24-h ambulatory ECG recording was performed at rest using a two-channel recorder during the same week as right heart catheterization. All recordings were analyzed using the Oxford Medilog Excel 5-1 HRV system with manual edition and correction of RR intervals and QRS. Tapes were eligible if they had at least 20 h of analyzable data.

The time domain analysis of HRV included Mean RR [mean duration of all normal-to-normal (NN) intervals, ms], SDNN (standard deviation of all NN intervals, ms), SDANN (standard deviation of the averages of NN intervals in all 5-min segments, ms), rmsSD (square root of the sum of the squares of differences between adjacent NN intervals, ms) and pNN50 (number of NN intervals differing by more than 50 ms from adjacent interval divided by the total number of all NN intervals, %).

The spectral analysis algorithm used a fast Fourier transformation. Data were analyzed in 10-min intervals throughout the recording. The results from each 10-min interval were averaged to form a composite spectrum. The range 0–0.5 Hz was represented by 1000 harmonics. The data were presented in non-linear scale (ms2). Frequency domain measurements included: total power (Tot P: 0-0.4Hz), very low frequency (VLF: 0.0033-0.04 Hz), low frequency (LF: 0.04-0.15 Hz) and high frequency (HF: 0.15-0.4 Hz). LF and HF were also expressed by LF/HF ratio [1].

2.3. Statistical analysis
All values are given as mean±standard deviation. Comparisons were made using the Mann–Whitney test. The Spearman test was used to correlate quantitative variables. A P-value <0.05 was considered statistically significant. STATVIEW 4.5 software (Abacus Concepts, Berkeley, CA) was used for statistical analysis.


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 5. Conclusion
 References
 
3.1. Characteristics of patients
Clinical data of patients with IDC and PPH and results of ECG, radionuclide ventriculography, hemodynamic investigations and 24-h ambulatory ECG are summarized in Table 1.


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  		Table 1 Clinical characteristics and results of investigations in patients with IDC and PPH

 
Patients with IDC had higher pulmonary capillary wedge pressure than patients with PPH (P=0.04), lower mean pulmonary artery pressure (P=0.006) and lower total pulmonary vascular resistance (P=0.0005). Measurements of HRV in the control group and in patients with IDC and PPH are shown in Table 2. All the measurement of HRV were significantly decreased in both groups of patients awaiting transplantation compared with the control group (IDC P<0.001, PPH P<0.01). However, the measurements of HRV were significantly lower in patients with IDC in the time domain for SDNN (P=0.003), SDANN (P=0.007), rmsSD (P=0.04) and pNN50 (P=0.04) and in the frequency domain for total power (P=0.01), VLF (P=0.03), LF (P=0.002) and HF (P=0.003).


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  		Table 2 Time-domain and frequency-domain measurements of HRV on 24-h ambulatory ECG in control group, in patients with PPH and in patients with IDC

 
There was no significant correlation between any measurements of HRV and left ventricular ejection fraction, right and left filling pressures or pulmonary vascular resistance during right heart catheterization in each group of patients with IDC or PPH and when considering both group of patients together (Fig. 1). Using multiple regression, no combination of hemodynamic parameters was significantly related to HRV measurements.


Figure 1
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  		Fig. 1 Lack of correlation between heart rate variability (total frequency power) and total pulmonary resistance or mean pulmonary artery pressure in both groups of patients with IDC and PPH.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
5. Conclusion
 References
 
To our knowledge, a decrease in HRV has not been previously described in patients with isolated right heart failure, normal left ventricular filling pressures and normal left ventricular ejection fraction. Respiratory central control and peripheral oscillation in respiratory movements might induce these effects on HRV. Moreover, these patients had a severe hemodynamic status and had very limited activity, with frequent bed rest and this may also explain the decrease in HRV compared with the control group who had limited activity but who were not recumbent. However, the results obtained in our study suggest that the severity of pulmonary hypertension and pulmonary vascular resistance may not be, by itself, a major determinant of the decrease in HRV, since patients with severe pulmonary hypertension in the PPH group had a less marked decrease in HRV measurements than patients with IDC who had lower pulmonary artery pressures and pulmonary vascular resistance. It has been shown that stretch of the sinoatrial node reduces high frequency HRV [9]. A possible explanation of the lower HRV in patients with CHF due to IDC could be that these patients have a pressure overload in the four chambers of the heart and may therefore have a more important recruitment of baroreceptors and/or volume receptors than patients with pressure overload limited to the right atrium and ventricle, even if the overload in these latter patients is more important than overload in the right chambers of patients with CHF.

No correlation was found between any measurements of HRV and right and left filling pressures during right heart catheterization in patients with IDC or PPH and when considering both group of patients together. These results seem to contradict some previous studies of coronary artery disease or CHF, including patients with variable CHF severity. It should be noted that all the patients in our study had severe hemodynamic status and this may in part explain the lack of correlation we have found. A relationship between hemodynamic status and HRV is found only when there is a wide range of values for both parameters, whereas it may not exist in patients with similar severe hemodynamic status [6]. However, we think that the fact that patients with severe PPH had a lower decrease in HRV measurements than patients with IDC is direct evidence of this lack of correlation. One can therefore suggest that pulmonary hypertension and resistances do not directly contribute to the decrease in HRV in heart failure.

A study by Mortara et al. has suggested that breathing disorders are not uncommon in congestive heart failure and they are associated with an increase in the VLF power which can affect measurement of HRV [10]. It was found that VLF accounted for 55% of total HRV in subjects with normal breathing, whereas VLF was 77% and 87% of Tot P in patients with periodic breathing or Cheyne–Stokes respiration, respectively. In our study, the ratio of VLF to Tot P was 50% for the control group, it was 53% in patients with PPH and also 53% in patients with IDC, thus similar to subjects with normal breathing in the study by Mortara. It appears therefore that our study was not affected by this confounding effect. It should be noticed that the difference was less significant between patients with IDC and PPH for total power than for SDNN, whereas these two parameters give similar information about overall HRV from a theoretical point of view. The technical explanation might be that total power in this study was the average of the total power of each 10-min period, thus excluding the ultra low frequency power of HRV.

The two groups of patients with IDC and PPH did not have the same treatment at the time of the ambulatory ECG recording. However, all the patients had severe heart failure and were awaiting transplantation. From an ethical point of view, it was difficult to stop these treatments and it should be considered that none of the previous studies about HRV in heart failure was performed without medical treatment. The effects of calcium-channel blockers on overall HRV seem to be limited, although only a few studies have focused on this topic [11–13]. On the contrary, it is known that ACE inhibition and digoxin may increase heart rate variability [14–17]. We do not think that this point affects the main conclusions of our study, since one can suggest that patients with IDC might have even lower HRV if they were not receiving ACE inhibitors and digoxin, thus increasing the difference compared with patients with PPH.

In a previous study of the general characteristics of HRV in IDC we found that analysis of HRV in association with hemodynamic parameters allows better identification of patients at high risk of cardiac death or heart transplantation [8]. The independent prognostic value of a decrease in HRV for outcome, that we found in patients with IDC, raises some questions about the underlying pathophysiological mechanisms involved in this decrease. The consideration that a decrease in HRV is a reflection of the alteration of the hemodynamic status appears too simple in light of the present results. Animal studies have suggested that early autonomic imbalance in the history of CHF may play an important role in the progression of circulatory failure or may even contribute to the development of cardiomyopathy in specific situations [18,19]. We have also found that patients with IDC without CHF already have a decrease in HRV [3]. One should therefore consider that the decrease in HRV in patients with CHF is not only a result of the hemodynamic alterations but that there are complex interactions between impairments of cardiopulmonary circulation and baroreflex sensory and sympathetic activation leading to a maladaptive and deleterious process revealed by measurements of HRV [1,20,21].

The effects of hormones such as adrenaline, aldosterone and brain natriuretic peptide on sympathovagal balance is important, but we did not have these measurements. These results would have been very interesting but they were not necessary for our main analysis of the relationship between the decrease in HRV and pulmonary hypertension. The patients in this study were all transplant candidates and our results may not apply to patients with less severe chronic left or right heart failure. Lastly, the more important and clinically relevant question is whether HRV can predict short-term mortality and arrhythmic death in patients with severe heart failure. It has already been found that a decrease in HRV was a predictor of cardiac death in chronic heart failure of various etiologies [4] and of major arrhythmic events in heart failure due to IDC [22], but this has not been demonstrated in transplant candidates. Moreover, the mechanism of sudden death is different in IDC and PPH since it is usually not related to ventricular arrhythmias in PPH.


   5. Conclusion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
 5. Conclusion
References
 
HRV is decreased in patients with isolated right heart failure due to PPH. However, HRV is more decreased in patients with IDC than in patients with PPH, despite lower pulmonary vascular resistance. This suggests that the decrease in HRV might be more pronounced in patients with pressure overload in both right and left atria and/or ventricles and that the increase in pulmonary vascular resistance is not the main causal factor behind a decrease in HRV in patients with heart failure. The hypothesis that a decrease in HRV is mainly a reflection of the deterioration in the hemodynamic status, as previously described in CHF, remains open to discussion.


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

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