Sympathetic nervous system, systolic heart failure, and central sleep apnea: Are we about to find the missing link?
Sympathetic nervous system, systolic heart failure, and central sleep apnea: Are we about to find the missing link?
Olivier Lairez 0 3
Damien Legallois 0 1 2
Denis Agostini 0
0 Reprint requests: Denis Agostini , MD, PhD , Service de Me ́decine Nucle ́aire, CHU Coˆte de Nacre , Caen , France
1 Service de Cardiologie, CHU Coˆte de Nacre , Caen , France
2 Service de Me ́decine Nucle ́aire, CHU Coˆte de Nacre , Caen , France
3 De ́partement de Me ́decine Nucle ́aire , CHU Rangueil, Toulouse , France
Sympathetic nervous system (SNS) activation has
long been known to be a cardinal feature in the
pathophysiology of cardiac remodeling and systolic heart
failure (SHF). It was reported to have implications for
both disease progression and survival. SNS activation is
assumed to be secondary to the decrease of
sympathoinhibitory reflexes usually drove by the stimulation of
afferent mechanoreceptors and by the increase of
efferent sympatho-excitatory mechanisms associated
with alteration in autonomic regulation.1 Activation of
cardiac and peripheral sympathetic nervous systems has
been linked to the rate of disease progression and sudden
death.2 The main retrospective and prospective studies
have shown that cardiac neuronal uptake based on
Heart-Mediastinum Ratio (HMR) by
123I-Metaiodobenzylguanidine (MIBG) imaging was a prognostic
indicator of severe heart failure and/or ventricular
arrhythmia if HMR was less than 1.6 in patients with a
left ventricular ejection fraction less than 35%.3-5 These
findings have been the rationale for the use of
betaadrenergic blocking agents in the management of
patients with SHF.
Several observations have suggested that ventricular
systolic dysfunction per se was not the principal
stimulus to sympathetic activation. If the decrease of
sympatho-inhibitory reflexes is directly linked to the
ventricular systolic dysfunction though the decrease of
the cardiac output, mechanisms underlying the
autonomic dysregulation seem more generalized. Among the
parameters acting on nonbaroreflex-mediated
sympathoexcitation, sleep-disordered breathing is one of the main
SYSTOLIC HEART FAILURE AND CENTRAL SLEEP
Sleep-disordered breathing is highly prevalent in
patients with SHF: central sleep apnoea with Cheyne
Stokes respiration (CSA-CSR) occurs in about a third of
patients with SHF.6 CSA is characterized by repetitive
suspension (apnea) or reduction (hypopnea) of
breathing, causing intermittent oxygen desaturation.
Interestingly, improving cardiac function through
medications, devices or surgery relieves CSA-CSR.6 It is
considered that CSA-CSR is a marker of greater heart
failure severity and probably an independent risk factor
for mortality.6 SNS activation likely contributes to this
increased risk of adverse cardiovascular events.
CENTRAL SLEEP APNOEA AND SYMPATHETIC
NERVOUS SYSTEM ACTIVATION
Central sleep apnea has deleterious effects includ
ing activation of different set of stimuli to the SNS.7
Hypoxia and hypercapnia induced by repetitive apnea
and hypopnea interrupt the normal tonic inhibition of
efferent sympathetic activity form pulmonary receptors,
leading to an increase in sympathetic discharge.8 Higher
rates of cardiac and total body norepinephrine spillover
were reported in subjects with CSA than in heart failure
patients without CSA.9 Ventricular remodeling, heart
failure progression, and consequently sudden death are
long-term consequences of sustained adrenergic
DOES ADAPTIVE SERVO-VENTILATION AND SUBSEQUENT ELIMINATION OF CENTRAL SLEEP APNEA CAN BE BENEFICIAL IN PATIENTS WITH SYSTOLIC HEART FAILURE?
CSA have adverse cardiovascular effects that are
reversed with adaptive servo-ventilation (ASV). ASV
has been shown to improve cardiovascular function in
CSA patients in small randomized clinical trials.6 But
the benefit of ASV for the purpose of extending life is
still controversial.11 Recent multinational randomized,
controlled trial has suggested that ASV increases
allcause and cardiovascular mortality in patients who had
SHF.12 This result opened an interesting discussion of
whether CSA-CSR reflects worsening heart failure or it
is an adverse risk factor for death in its own right.13,14
DOES ELIMINATION OF CENTRAL SLEEP APNEA
FORESTALL OR REVERSE SYMPATHETIC
Treatment of patients with heart failure and CSA
with ASV attenuates the magnitude of SNS activation.15
However, it is important to consider that the alteration in
autonomic regulation, which occurs early during the
course of heart failure, is selective, rather than
generalized.16 This complex pathophysiology, linking SNS
activation, CSA, and SHF, leads to temporal, regional,
and inter-individual heterogeneity of SNS activation.1
Consequently, exploration of local cardiac sympathetic
nerve activity is determinant point in the understanding
of the effects of ASV on CSA and SHF.
In the current issue of the Journal, Toyama et al.
evaluated the impact of ASV on cardiac sympathetic
nerve activity assessed by 123I-MIBG imaging and
functional capacity in patients with SHF. They
prospectively randomized 31 consecutive patients with both SHF
and CSR-CSA between groups with or without ASV for
6 months in addition to guideline-based medical
management for heart failure. The authors show that ASV
decreases apnea-hypopnea index, which is accompanied
by a decrease of the total defect score and the washout
rate, and an increase in the heart-to-mediastinum activity
ratio of the 123I-MIBG images. Furthermore, the patients
with ASV show a decrease of the total mismatch score
between the 123I-MIBG images and the 99mTc-MIBI
images. These effects on cardiac sympathetic activity
were accompanied by an improvement in functional
parameters as showed by the increase in left ventricular
ejection fraction, and the decrease in NHYA functional
class and the specific activity scale. In contrast, the
patients without ASV showed no change in any of these
parameters. This study demonstrates the beneficial
effects of ASV therapy on cardiac sympathetic nerve
activity, cardiac function, and functional capacity, as
well as apnea-hypopnea index, over a period of
6 months. These results highlight the link between
CSA reduction and reversion of cardiac sympathetic
discharge. Only one study had previously assessed the
impact of ASV on cardiac sympathetic activity by
exploring the effects of ASV on cardiac norepinephrine
spillover.17 The gain of 123I-MIBG over circulating
catecholamine dosage is to explore the mean effect of
ASV on cardiac sympathetic activity and not only the
acute effect, which is reflected by the half-life of the
catecholamine. As mentioned previously, the autonomic
dysregulation that accompanying SHF has temporal,
regional, and inter-individual heterogeneity and requires
long term rather than acute evaluation. With their study,
Toyama et al. show that the benefit of ASV on cardiac
sympathetic activity is sustained over the time. Finally,
these results are going versus the compensatory theory,
which suggest that CSA is a compensatory mechanism of
SHF rather than comorbidity.
This evidence of the beneficial effects of ASV on
cardiac sympathetic nerve activity and functional
capacity in patients with both SHF and CSA, questions about
the contradictory results of the SERVE-HF trial.12 The
benefit of ASV depends probably on the basal level of
cardiac sympathetic activity. Univariate subgroup
analyses from the SERVE-HF trial provide some points to
consider: when baseline left ventricular ejection fraction
was [30%, the data suggested that the cardiovascular
safety signal for ASV might disappear.18 This analysis
suggests that ASV therapy benefits only for the more
severe patients. As 123I-MIBG images are well
correlated with left ventricular ejection fraction, we can
suppose that, in the future, 123I-MIBG could be use as a
tool for the selection of patients with SHF who will
benefit from ASV therapy. Further work investigating
the place of 123I-MIBG images for the selection and the
monitoring of patients with SHF who will benefit from
ASV therapy is needed.
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