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European Journal of Heart Failure 2001 3(2):197-202; doi:10.1016/S1388-9842(00)00139-2
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© 2001 European Society of Cardiology

Different baseline sympathovagal balance and cardiac autonomic responsiveness in ischemic and non-ischemic congestive heart failure

Gabriella Malfatto*, Giovanna Branzi, Selene Gritti, Luca Sala, Renato Bragato, Giovanni Battista Perego, Gastone Leonetti and Mario Facchini

Divisione di Cardiologia, Istituto Scientifico Ospedale San Luca, Istituto Auxologico Italiano IRCCS, Università di Milano Milan, Italy

* Corresponding author. Tel.: +39-2-58-21-61; fax: +39-2-58-21-6-712. E-mail addrress: malfi{at}auxologico.it (G. Malfatto).


   Abstract
Top
 Abstract
1. Introduction
 2. Methods
 3. Results
 4. Discussion
 References
 
Background: A profound autonomic unbalance is present in heart failure: its correlation with the etiology of the disease has never been investigated.

Aims: We characterized the sympatho-vagal balance and autonomic responsiveness of 42 patients (21 with ischemic heart failure, 21 with idiopathic dilated cardiomyopathy). Patients had comparable NYHA class, ejection fraction, exercise pVO2, exercise ventilatory response, incidence of β-blocking treatment. None showed periodic breathing or nocturnal arterial desaturation.

Methods: Heart rate variability was assessed in the time and frequency domain during: (1) 10 min of quiet supine resting and free breathing; (2) 10 min of regular breathing at a frequency of 20 acts/min (= parasympathetic stimulus); and (3) 10 min of active standing (= sympathetic stimulus). The ratio of the low- to high-frequency components of each autospectrum obtained in the frequency domain (LF/HF) was used as an index of sympathovagal balance.

Results: Patients with ischemic heart failure had a greater baseline sympathetic activation (higher LF/HF) than those with idiopathic dilated cardiomyopathy, maintaining some parasympathetic responsiveness as well (reduced LF/HF with regular breathing).

Conclusions: There is a distinct autonomic control according to the etiology of heart failure, a finding that may help understanding its pathophysiology, and could be useful in the clinical management of patients.

Key Words: Autonomic nervous system • Sympatho-vagal balance • Heart failure • Ischemic heart disease • Idiopathic dilated cardiomyopathy

Received April 13, 2000; Revised July 15, 2000; Accepted October 12, 2000


   1. Introduction
Top
 Abstract
 1. Introduction
2. Methods
 3. Results
 4. Discussion
 References
 
An abnormal autonomic control of cardiovascular function, with signs of sympathetic activation [1], parasympathetic withdrawal [2,3] and peripheral organ unresponsiveness [4], has been described in patients with congestive heart failure. This neurohormonal derangement may have a central role in the progressive impairment of myocardial function: moreover, the level of circulating catecholamines seems strongly related to the prognosis [1,5]. In recent years, the analysis of heart rate variability in the time and frequency domain has been applied to the study of neural cardiovascular control in heart failure. This technique has also provided useful information about the pathophysiology of the failing heart [6–8] and, similarly to what has been demonstrated for patients after myocardial infarction [9–11], it has also been used in risk stratification [12,13]. Although similar proportions of patients with ischemic and non-ischemic heart failure were present in many reports [4,6,8], in none of the studies analyzing heart rate variability, the etiology of heart failure has been considered as a potentially relevant determinant of the patients’ autonomic profile. In fact, ischemic and non-ischemic heart failure share a similar clinical presentation, but their response to the newest drug therapies is sometimes dissimilar [14,15], suggesting a fairly distinct pathophysiology. In a recent report, the time-domain pattern of heart rate variability differed in patients with ischemic compared with patients with idiopathic cardiomyopathy [16]. We thus investigated whether the etiology of congestive heart failure could influence the sympathovagal balance and the autonomic responsiveness of patients with mild to moderate congestive heart failure. Preliminary data have been presented [17].


   2. Methods
Top
 Abstract
 1. Introduction
 2. Methods
3. Results
 4. Discussion
 References
 
We studied 42 patients with clinically stable heart failure, not enlisted for heart transplantation, who entered an exercise rehabilitation program. Exclusion criteria for the study were: diabetic neuropathy, atrial fibrillation, and/or severe ventilatory impairment. Heart failure was ischemic in 21 patients and non-ischemic (idiopathic dilated cardiomyopathy) in 21. Ischemic heart failure was defined if patients had a history of myocardial infarction, coronary artery bypass surgery, or both, together with absence of residual ischemia and/or myocardial viability. Idiopathic dilated cardiomyopathy was defined if no history of hypertension or cardiac valves pathology were present, and a normal coronary angiography was obtained within 6 months from our study. Patients’ characteristics are summarized in Table 1. The two groups had comparable NYHA class and left ventricular ejection fraction (EF). Cardiopulmonary exercise stress test, obtained in all patients (Vmax 2900, SensorMedics Inc, USA) [18] also showed similar exercise pVO2, anaerobic threshold (AT), ventilatory response to exercise (VE/VCO2 ratio). Therapy with the β-blocker carvedilol (25–75 mg/day) was equally distributed too (more than half of the population). None of the patients showed either periodic breathing or nocturnal arterial desaturation, as determined during a preliminary, brief hospitalization. It was important to exclude these two conditions, because an abnormal central respiratory pattern may account for most of the periodic oscillations in the heart period in patients with heart failure [8,19], and can therefore interfere with the analysis and interpretation of the heart rate variability data obtained with spectral techniques [20,21].


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  		Table 1 Clinical characteristics of the two groups of patients

 
Heart rate variability in the time and frequency domain was assessed [22,23] during: (1) 10 min of quiet supine resting and free breathing; (2) 10 min of regular breathing at a frequency of 20 acts/min (activation of the predominantly parasympathetic cardiopulmonary receptors [25]); and (3) 10 min of active standing (sympathetic orthostatic stimulation [22]). We used commercial software (PREDICTOR II, Corazonix Ltd, Oklahoma City, OK, USA); analog ECG signal was digitized at 500 Hz; QRS complex was recognized by cross-correlation with a template. Premature beats and the subsequent interval were automatically discarded, and this detection was also visually checked. To obtain a measure of heart rate variability comparable with that reported in other studies [12,13], we considered the standard deviation of RR intervals (RRSD), a widely used time domain index [23]. The autoregressive algorithm used DC filtering and an Akaike model between 20 and 24. Boundaries of the low-frequency oscillation (LF=0.03–0.15 Hz) and of the high-frequency oscillation (HF=0.15–0.40 Hz) were chosen by the investigator: their area was calculated by the software, and converted into normalized units (n.u.) to better identify the individual spectral component [6,22,23]. The amount of LF and HF oscillation (in n.u.) and their ratio LF/HF were calculated. The short-time autospectra of this group of patients with a normal breathing pattern did not show the very-low-frequency component (VLF: 0.00–0.03 Hz) that is probably linked to abnormal respiration and cyclic arterial desaturation [8,19,20]: as discussed above, both phenomena were absent in the study patients. The ratio LF/HF of each autoregressive power spectrum was used as an index of sympathovagal balance. We choose this index instead of the more popular and extensively applied time domain variables [9,11,23] because there is convincing evidence that this index represents a solid and reliable tool for pathophysiological investigations on autonomic cardiovascular regulation [6,21–25].


   3. Results
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
4. Discussion
 References
 
At rest, all patients showed signs of increased sympathetic activation and blunted parasympathetic tone both in the time and in frequency domain (RRSD reduced to 36±16 ms, LF/HF increased to 8.5±0.9). During regular breathing and sympathetic stimulation, RRSD was unchanged (regular breathing=38±10 ms, standing=42±12 ms, NS), whilst spectral analysis revealed a preserved response of patients to regular breathing (LF/HF=4.6±0.5, P<0.05) and no response to orthostatic sympathetic stimulation (LF/HF=8.3±1.2) (Fig. 1). Confirming previous observations [16], RRSD was inversely related to the ventilatory response to exercise expressed as VE/VCO2 (Fig. 2). No relationship was found between LF/HF (and its shifts with the various stimuli) and VE/VCO2, peak oxygen consumption, VO2 at anaerobic threshold, ejection fraction or left ventricular volumes.


Figure 1
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  		Fig. 1 Example of the power spectrum of a patients with clinically stable heart failure of ischemic origin (anterior MI 10 years earlier, CABG the following year, no residual ischemia/viability demonstrated with dobutamine-echocardiography), being treated with enalapril, 40 mg/day; ASA, 160 mg/day; and isosorbide mononitrate, 60 mg/day. The autospectrum showed a predominant low-frequency component at rest, a distinct increase of the high-frequency component during regular breathing, and again a prevailing low-frequency component during standing. This pattern represents the average response of all patients, but there were differences between those with ischemic and non-ischemic origin (see text for discussion).

 


Figure 2
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  		Fig. 2 Relationship between the ratio VE/VCO2 at peak of cardiopulmonary exercise stress test and RRSD at rest. A negative relationship was present, similar to what has been described between VE/VCO2 and other time-domain variables [16].

 
When patients’ autonomic profiles were analyzed taking into account the etiology of heart failure, again RRSD was similar at baseline and during the various autonomic challenges. On the other hand, a different behavior was observed in the two groups when LF, HF and LF/HF were considered (Table 2). Patients with ischemic heart failure had a greater sympathetic activation at rest than patients with non-ischemic origin, and showed a significant reduction of LF/HF during controlled respiration. At variance, patients with idiopathic dilated cardiomyopathy had a baseline sympathovagal balance showing lower adrenergic activation, and they did not modify their autonomic tone during either controlled breathing or during orthostatic stimulation (Fig. 3).


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  		Table 2 RR standard deviation and spectral density of RR intervals in patients

 


Figure 3
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  		Fig. 3 Mean values of LF/HF ratio in the three experimental conditions. Patients were divided according to the etiology of heart failure: the greater sympathetic activation and the persistence of an autonomic modulation during regular breathing are evident in the group of ischemic origin.

 

   4. Discussion
Top
 Abstract
 1. Introduction
 2. Methods
 3. Results
 4. Discussion
References
 
In this study we examined whether the etiology of heart failure could affect the sympatho-vagal balance at rest and during ventilatory and orthostatic challenges. We found indeed that some differences existed that in our opinion deserve some comments.

We confirmed that patients with heart failure, relatively independent from NYHA class, have low values of RR standard deviation, i.e. the commonest used time domain index of heart rate variability in clinical studies [12,13]. Moreover, we also found a significant relationship between the degree of impairment in ventilation and a progressive reduction in RR intervals variability [16]: this further indicates that sinus arrhythmia is a good general index of the heart–lung interaction [27]. However, while RR standard deviation was not changed when examined during autonomic stimulation, nor it did differ in the two groups of patients, spectral analysis revealed an interesting behavior of autonomic tone both at rest and during various tests, depending on the origin of the disease: patients with ischemic cardiomyopathy had a higher sympathetic tone at rest and still showed parasympathetic responsiveness. Thus, spectral analysis could be superior to time domain analysis in unveiling different pattern of RR fluctuation within the same total variability [22,23].

In partial contrast with previous observations on patients with symptomatic moderate heart failure [6,7], we found signs of sympathetic hyperactivity with a prominent LF component in patients, despite the fact that half of them were in NYHA class III and 33% had a pVO2 between 10 and 15 ml/kg/min (see Table 1 and Fig. 1): in none of them the LF component of the autospectrum was small or absent. In previous studies, the prevalent therapy was the traditional association of digitalis and diuretics [6,7]. On the contrary, none of our patients was on digitalis, according to the new recommendations of the international guidelines for subjects with heart failure in sinus rhythm [26], while they were all being treated with ACE inhibitors, and more than half were also on β-blockers. These drugs have a profound impact on clinical conditions and on survival in patients with heart failure: as in the case of patients after myocardial infarction [27,28], they may also improve the cardiovascular autonomic control. Under treatment with ACE-inhibitors and β-blockers, the sinus node may thus regain its responsiveness to circulating catecholamines and to central commands [29,30], unveiling an exceeding sympathetic activation. We thus speculate that in patients with ischemic cardiomyopathy, sympathetic tone is higher at rest than in patients with idiopathic dilated cardiomyopathy because of the summation of a generalized neurohormonal derangement with specific cardio-cardiac sympathetic reflexes, arising from the mechanical activation of nervous afferent fibers in healthy myocardial areas adjacent to areas of abnormal or absent contraction [30–32]. According to this reasoning, the maintained autonomic response during controlled respiration in patients with ischemic heart failure might follow a similar pattern of simultaneous stimulation of vagal pulmonary and cardiac mechanoceptors [32]. Of note, being purely mechanical in origin, this chronic sympathetic activation does not need an ischemic stimulus: in fact, none of the patients had signs of persistent myocardial ischemia. We also confirmed that all patients had a blunted sympathetic reactivity to orthostatic stimulation: a typical, although non-specific, pattern observed in many pathological conditions: hypertension [33], recent myocardial infarction [34], diabetes [35], asymptomatic left ventricular dysfunction [36].

In conclusion, patients with clinically stable, moderate heart failure showed a significantly different impairment in autonomic control in resting conditions and during stimulation of cardiopulmonary receptors, depending upon the etiology of the disease. This information may help understanding the pathophysiology of heart failure especially in its early, asymptomatic or poorly symptomatic phases. Its relevance in the clinical management of patients and its prognostic significance must be established with large prospective studies.


   Acknowledgements
 
We are grateful to the physical therapists Barbara Avezzù MS, Maria Teresa Femminis MS, Alberto Gandolfo MS, Veronica Sagace, MS and to Ada Spiezia RN, for their care of the patients undergoing rehabilitation in our institution.


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

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