Introduction
Patients with systolic heart failure (HF) often present with an unstable respiratory pattern characterized by alternating phases of hyperventilation and central apneas (CA), also named Cheyne-Stokes respiration (CSR) [
1‐
3]. CSR is mainly caused by increased chemosensitivity to either hypoxia or hypercapnia [
4] and delayed chemoresponse due to the prolonged circulatory time that directly results from decreased cardiac output [
5]. While the former seems to influence CSR severity, the latter seems to rather influence CSR cycle duration, and the duration of the hyperventilation phase in particular [
5]. It has been hypothesized that CSR alters sympathovagal balance (SVB) in favor of increased sympathetic drive and thus has detrimental effects in HF when left untreated [
3,
6]. This may be mainly due to an altered pulmonary stretch reflex and blunted vagal stimulation [
6,
7], but also due to chemoreflex-mediated sympathetic overactivity in response to apnea-related hypoxemia and hypercapnia [
7,
8]. SVB is known to play a key role in determining HF progression because medications that decrease sympathetic drive have been shown to have favorable effects on outcome [
9,
10]. For this reason, CA has been considered a potential therapeutic target in HF and has been treated using a variety of options, including oxygen therapy [
11], carbon dioxide (CO
2) rebreathing [
11,
12], acetazolamide [
13‐
15], and nocturnal mask-based therapies such as continuous positive airway pressure [
16] or adaptive servo-ventilation [
17,
18].
The results of the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo Ventilation in Patients with Heart Failure (SERVE-HF trial) [
19] have challenged this hypothesis, because patients with systolic HF (left ventricular ejection fraction [LVEF] ≤ 45%) and CSR treated with adaptive servo-ventilation unexpectedly showed increased mortality compared with controls who received optimal medical therapy alone [
20,
21]. This finding has led to controversy about the effect of CSR in HF as potentially compensatory rather than harmful, at least in a subset of patients [
20,
21]. Potential favorable effects of CSR are thought to include an increase in venous return and cardiac output, and positive effects of hypocapnia on SVB during the hyperventilation phase [
22,
23].
The net effect of CSR, which is characterized by alternating cycles of hyperventilation and CA may be influenced by several factors. These include the relative duration of the hyperventilation and CA phases, as well as background cardiac hemodynamics and/or feedback resetting. CA is also seen, albeit less frequently, in subjects in whom no overt cardiac or neurological cause can be identified, where it is called idiopathic central apnea (ICA) [
24]. In patients with ICA, apneic events are usually associated with increased sensitivity of the chemoreflex and are characterized by shorter cycle duration resulting from normal cardiac output and circulation time [
25]. ICA may also potentially alter SVB, either directly or indirectly (by altering sleep quality), but this (along with its potential hemodynamic effects) has not yet been investigated.
This study investigated the immediate effects of CA on SVB and hemodynamic parameters during stage 2 non-rapid eye movement (NREM) sleep (N2) in patients with HF-related CA and ICA. This approach allows evaluation of whether the effects of CA on both the autonomous nervous system and the cardiovascular system during sleep differ between patients with and without systolic HF. Thus, it would theoretically be possible to identify a mechanism by which CA potentially exerts beneficial effects in HF patients.
Discussion/conclusion
This is the first study to comparatively investigate the effects of spontaneous CA on SVB and hemodynamics in both HF and ICA patients at night, after adjusting for sleep stage. The most important finding of this study is that the impact of CA on SVB seems to be different depending on the underlying hemodynamic conditions or the presence of HF. In patients with HF, CA had almost neutral effects on SVB compared with NB during N2 sleep. In contrast, in subjects with ICA, CAs were associated with an increase in the VLF component of dBPV. While some oscillatory variations of dBP can be detected within a single cycle of hyperventilation and apnea (either CA in the context of HF, or ICA), when comparing the phases of ventilatory instability to those of NB, an overall neutral hemodynamic effect was observed in both HF patients and heart-healthy subjects.
Transition from wakefulness to sleep was characterized by a decrease in HR and by a shift in HRV (but not BPV) towards vagal predominance over sympathetic control (increased high frequency component, decreased LF, and decreased HF/LF) in heart-healthy subjects, as expected and consistent with a previous study [
39]. The same transition was accompanied by a decrease in only HR in patients with HF, while no changes were observed in HRV and BPV, a finding which may be in line with an overall decreased circadian modulation of different physiological signals in HF [
3,
6,
9].
It has been hypothesized that CA further increases sympathetic drive in the setting of HF, thus exerting harmful effects if left untreated [
4,
40]. Nonetheless, a previous study which applied both polysomnography and right heart catheterization showed that cardiac norepinephrine spillover was mainly related to HF severity rather than to CA severity (based on the AHI) [
41]. Moreover, the SERVE-HF trial surprisingly showed that effective suppression of CA during treatment with adaptive servo-ventilation might result in increased mortality [
19‐
21]. This finding gave rise to the hypothesis that CSR may exert compensatory rather than detrimental effects in patients with HF [
20,
21]. In particular, Naughton suggested that the hyperventilation phase may enhance stroke volume and attenuate excessive SNA with “physiological features more likely to be compensatory and beneficial than injurious in HF” [
22].
We tested this hypothesis by measuring the immediate effects of a CA breathing pattern on SVB and hemodynamics during N2 sleep in HF patients. At least in this cohort of HF patients with only mild to moderate CA, these effects turned out to be neutral; i.e., no significant differences between relevant parameters were found when periods of CA were compared with NB. Patients with HF typically show a CSR pattern, and unstable breathing is characterized by repetitive cycles of hyperventilatory and apneic phases. A possible interpretation of this finding may therefore be that whatever the effect of CA on SVB and cardiac hemodynamics is, this is compensated and counterbalanced during the hyperventilation phase. However, in heart-healthy subjects with normal cardiac output and ICA, an increase in the VLF component was still observed when the same sleep stage was compared with NB.
Three explanations may help explain this finding. Firstly, CA characteristics are different in patients with and without HF (e. g., cycle duration in HF-related CA is 1–2 min vs. 30–45 s in ICA) [
5,
24,
25]. Since hypocapnic hyperventilation is likely to attenuate excessive sympathetic drive, longer hyperventilatory phases in HF would explain why the net effect on SVB was neutral in CA due to HF but not in ICA (i.e., due to longer compensatory hyperventilation in HF). Secondly, even similar CAs may result in different autonomic response in patients with and without HF, depending on the background chemoreflex activity and its interaction with other cardiopulmonary reflexes during oscillatory breathing. In particular, HF leads to resetting of several feedback circuits due to forward (hypoperfusion of carotid bodies and kidneys) and backward failure (increased left atrial pressure). Indeed, a previous study from our group pointed towards this theory. Applying simulation of a CSR breathing pattern, it was shown that CSR results in neutral changes effects on SVB in patients with HF [
36]. Thirdly, the effects of HF treatment, especially β-blockers, have been previously been shown to dump the firing of sympathetic outflow on peripheral targets (i.e., heart and vessels). Similar effects of β-blocker treatment were obvious in the current study since sympathetic drive was decreased in the awake state in HF compared with ICA patients.
In both patients with HF-related CA and those with ICA, CAs were found to be associated with slight decreases in HR, sBP, and dBP compared with pre-apneic (hyperventilation) levels. These findings support data from physiologic studies of Burnum et al. and a previous study from our group [
42,
43], and are also in line with the oscillatory behavior observed in the pulmonary circulation [
42]. It is currently unknown whether the net effect of alternating phases of apneas and hyperventilation will always be neutral on sympathovagal balance (as observed in our HF cohort) or also cause a drift in some physiological variables in subjects with different chemoreflex and/or plant gain, circulatory delay, or in different sleep stages. This should be addressed by future studies that should also ideally include some direct measurement of sympathetic outflow, such as cardiac sympathetic nerve recordings in animals or muscle SNA in humans.
Despite its comprehensive approach, this study has, in our opinion, five main limitations. Firstly, previous validation studies using the same non-invasive hemodynamic monitor were only performed in free breathing conditions. Therefore, the results obtained during different breathing maneuvers should be interpreted with caution, especially SVI, CI, and TPRI [
27‐
29]. Nonetheless, even invasive hemodynamic recordings would include uncertainties compared with a steady-state condition, especially when rapid transition from one phase to the other is evaluated (i.e., from hyperventilation to apnea). Secondly, SNA was not measured invasively in this study, i.e., by direct recording of MSNA. Non-invasive recording of HRV and BPV can only provide an indirect measure of SNA. Therefore, it is impossible to understand whether there is a problem of nerve firing or organ response. However, close correlation between MSNA and non-invasive SNA surrogate markers has previously been shown, both in heart-healthy volunteers [
44] and HF patients [
45], and performance of MSNA during sleep is technically difficult, especially for long recordings. Thirdly, rather short recordings of CA breathing patterns (i.e., 10 min in length) were chosen to assess the effects of CA on SVB. Hence, we cannot exclude that longer periods of CA would increase sympathetic drive in patients with HF. Fourthly, these results are not applicable to different sleep stages and the CA alteration of sleep architecture may also be a cause of HRV/BPV changes during the whole night, as previously described [
46]. Finally, our findings may be different in larger populations with more severe CA, different LVEF, background hemodynamics, and feedback set point ideally also measuring MSNA and corrrelating it with the extent of hypocapnia in HF [
47]. Hence, neutral findings in the present study must be interpreted again with caution considering the small sample size and pre-selection for the presence of CAs that were “only” present in 20–30% of the 10 minutes of the 10-min time segments evaluated. Taking into account the statistical assumption behind the calculation of the Bonferroni post hoc corrections for multiple
t tests, actual
p values reported in Tables
3 and
4 should be interpreted with caution.
In conclusion, CA during sleep is associated with acute hemodynamic effects compared with hyperventilation in both patients with HF and subjects with ICA. When comparing phases of unstable ventilation to those of stable ventilation, no significant change in SVB and hemodynamics was observed in patients with systolic HF, while an increased VLF of dBPV was observed in heart-healthy subjects with ICA. The different effects of CA in different clinical conditions should be thoroughly investigated in future studies to understand if, and in which cases, they may represent a risk and consequently a promising therapeutic target.
Compliance with ethical standards
Comments
Spiesshoefer et al. describe different autonomic changes during central apneas in patients with systolic heart failure compared to central apneas in patients with idiopathic central apneas. These findings are interesting and create the basis for future investigations. Further detailed description of central respiratory events and autonomic challenge testing may provide further information to assess, whether differences in central respiratory events or differences in autonomic responses to comparable central respiratory events contribute to the observation described in this manuscript. Additionally, further sleep and autonomic intervention studies are required to finally show, whether central sleep apneas in heart failure patients are really modifiable risk factors or a marker of underlying disease and autonomic imbalance.
Dominik Linz
Mainz, Germany
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