Neuroscience and Biobehavioral Reviews 74 (2017) 321–329

Contents lists available at ScienceDirect

Neuroscience and Biobehavioral Reviews

journal homepage: www.elsevier.com/locate/neubiorev

Review article

Sleep, sleep deprivation, autonomic nervous system and

cardiovascular diseases
Eleonora Tobaldini a,b , Giorgio Costantino a , Monica Solbiati a , Chiara Cogliati c ,
Tomas Kara d,e , Lino Nobili f , Nicola Montano a,b,g,∗
a
Fondazione IRCSS Ca’ Granda, Ospedale Maggiore Policlinico, Milan, Italy
b
Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
c
Department of Internal Medicine, L. Sacco Hospital, Milan, Italy
d
Division of Cardiovascular Diseases, Heart Hospital of Hamad Medical Corporation, Doha, Qatar
e
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
f
C. Munari Center of Epilepsy Surgery, Niguarda Hospital, Milan, Italy
g
International Clinical Research Center, St. Anne University Hospital, Brno, Czech Republic

a r t i c l e i n f o a b s t r a c t

Article history: Sleep deprivation (SD) has become a relevant health problem in modern societies. We can be sleep
Received 9 April 2016 deprived due to lifestyle habits or due to sleep disorders, such as insomnia, obstructive sleep apnea
Received in revised form 30 June 2016 (OSA) and neurological disorders.
Accepted 6 July 2016
One of the common element of sleep disorders is the condition of chronic SD, which has complex biolog-
Available online 7 July 2016
ical consequences. SD is capable of inducing different biological effects, such as neural autonomic control
changes, increased oxidative stress, altered inflammatory and coagulatory responses and accelerated
Keywords:
atherosclerosis.
Autonomic nervous system
Sleep deprivation
All these mechanisms links SD and cardiovascular and metabolic disorders. Epidemiological studies
Apnea have shown that short sleep duration is associated with increased incidence of cardiovascular diseases,
Cardiovascular diseases such as coronary artery disease, hypertension, arrhythmias, diabetes and obesity, after adjustment for
socioeconomic and demographic risk factors and comorbidities.
Thus, an early assessment of a condition of SD and its treatment is clinically relevant to prevent the
harmful consequences of a very common condition in adult population.
© 2016 Elsevier Ltd. All rights reserved.

Contents

1. Sleep physiology and autonomic nervous system (ANS) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322

2. Sleep deprivation: general aspects . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
3. Experimental sleep deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 322
4. Pathological sleep deprivation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 323
4.1. Pathological sleep deprivation and congestive heart failure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
4.2. Pathological sleep deprivation and hypertension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 324
4.3. Pathological sleep deprivation and coronary artery disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
4.4. Pathological sleep deprivation and atrial fibrillation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325
4.5. Pathological sleep deprivation and metabolic diseases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 326
5. Conclusions and perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
Acknowledgments . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 327

∗ Corresponding author at: Department of Clinical Sciences and Community

Health, University of Milan, Ospedale Maggiore Policlinico, via F. Sforza, Milan, Italy.
E-mail address: nicola.montano@unimi.it (N. Montano).

http://dx.doi.org/10.1016/j.neubiorev.2016.07.004
0149-7634/© 2016 Elsevier Ltd. All rights reserved.
322 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
1. Sleep physiology and autonomic nervous system (ANS)
Mammals spend around one-third of their lifetime sleeping.
Although the biological meanings of sleep process is still debated,
we know that sleep is a complex physiological event, which
involves several different biological pathways, from neural cortical
circuits to the heart (Saper et al., 2005; Tononi and Cirelli, 2006).
Most of the biological functions of the body changes during sleep
compared to wake, such as heart rate (HR), arterial blood pressure
(ABP), temperature, as well as hormonal secretion and immune
function. Cardiovascular regulation is profoundly modified dur-
ing sleep, and the interconnection between cardiovascular system
and sleep processes must be considered as a bidirectional link.
Cardiovascular diseases are associated with alterations of physi-
ological sleep and vice versa sleep disorders can importantly alter
the cardiovascular system, leading to an increased cardiovascular
risk (Kendzerska et al., 2014; Gami et al., 2013).
In this context, autonomic nervous system (ANS) plays a pivotal
role. In fact, during physiological sleep, HR and ABP lower during
non-REM sleep, with marked increases during REM sleep (Trinder
et al., 2001; Somers et al., 1993). These hemodynamic fluctua-
tions are expression of the autonomic cardiovascular modulation of
HR and ABP, due to sympathetic and parasympathetic oscillations
of the sympatho-vagal balance. A predominant vagal modulation
is observed during NREM sleep and a significant predominant
sympathetic control during REM sleep, at levels higher than in
wakefulness (Trinder et al., 2001; Somers et al., 1993). These data
have been confirmed by the direct recordings of sympathetic fibers
using microneurographic technicques (MSNA) (Somers et al., 1993)
and using the analysis of heart rate variability (HRV), which is a non
invasive tool able to detect the rhythmic oscillations embedded in
heart period and blood pressure time series (Montano et al., 2009).
HRV analysis identifies three main oscillatory components, very
low frequency (VLF), marker of hormonal and circadian oscillations,
low frequency component (LF), marker of sympathetic modulation,
and high frequency component (HF), marker of vagal modulation
and synchronous with respiration (Montano et al., 2009). HRV has
been widely used for the assessment of cardiovascular autonomic
control during sleep, showing a progressive decrease of LF compo-
nent, marker of sympathetic modulation, and a predominant vagal
control, as sleep becomes deeper (from wakefulness to deep NREM
sleep). On the opposite, REM sleep is characterized by a predomi-
nant sympathetic modulation with surges of sympathetic activity
at levels even higher than in wake (Brandenberger et al., 2003;
Legramante et al., 2003; Trinder et al., 2001; Tobaldini et al., 2014).
2. Sleep deprivation: general aspects
In the last decades, several studies have investigated the effects
of sleep deprivation (SD) on cardiovascular morbidity.
We know that we sleep less than in the past: in 1900 esti-
mated adult average sleep in US was nine hours, in 1980 seven
hours, in 2000 six and a half hours (Schoenborn and Adams, 2010).
National Institutes of Health recommends at least 10 h of sleep for
children, 9–10 h for teenagers, and 7–8 h for adults. It has been
reported that in 2014 almost 1/3 of the adults slept less than 6 h per
night (Schoenborn and Adams, 2010). Therefore, SD has become a
huge health care problem in modern societies. Why are we sleep
deprived? Several aspects must be taken into account. First, we can
be sleep deprived for reasons related to our lifestyle, such as the use
of electronic devices before going to sleep, which alter the physio-
logical secretion of melatonin (Ackermann et al., 2013), hard work
schedule, shift work etc. Second, we can be sleep deprived because
of ageing process, because ageing is associated with a reduction
of total sleep time and a disruption of physiological sleep. Third,
Fig. 1. Sleep deprivation (SD) can be due to lifestyle habits, sleep disorders and
experimental sleep protocols. Despite the origine, SD activates several physiopatho-
logical pathways, such as autonomic nervous system dysfunction, endothelial
dysfunction, increased inflammation, coagulation and oxidative stress resposnses,
deregulation of hormones secretion. All these alterations are thought to be respon-
sible for the link between SD and cardiovascular disorders.
we may suffer from a sleep disorders, namely a sleep disordered
breathing (SDB), insomnia, periodic limb movements (PLM), and
restless leg syndrome (RLS), to list just the more frequent.
It is important to underline that SD has important biological
consequences, which can cause significant cardiometabolic and
neurological sequelae. We will focus our review on the relationship
between SD and cardiometabolic changes.
3. Experimental sleep deprivation
Several epidemiological evidences suggest a link between short
sleep duration and an increased risk of developing cardiovascular
diseases, i.e. coronary artery diseases, congestive heart failure and
hypertension (Cappuccio et al., 2010), as well as infections (Patel
et al., 2012) and metabolic diseases (Tasali et al., 2008a,b).
These clinical consequences are due to the activation of differ-
ent biological pathways, such as a disregulation of the autonomic
cardiovascular control (Tobaldini et al., 2013a,b, 2014), an altered
inflammatory and immune response (Irwin et al., 2008; Meier-
Ewert et al., 2004; Imeri and Opp, 2009) and a deregulation of
leptin-ghrelin system and insulin sensitivity (Rafalson et al., 2010)
[see Fig. 1].
Several experimental protocols have been carried out to assess
the changes induced by both acute and chronic SD in healthy sub-
jects. Except for the study by Kato et al. (2000), it has been reported
that after a sleep loss of 24 h, ABP was significantly altered. Namely,
after a sleep loss of 24 h, HR and BP were higher compared to base-
line in healthy subjects (Sauvet et al., 2014; Sunbul et al., 2014;
Zhong et al., 2005). One of the possible mechanism involved in
these cardiovascular changes could be related to modification of
the ANS activity. The role played by ANS has been widely inves-
tigated in this setting and almost all the data in literature report
an increased sympathetic activity associated with acute SD. Zhong
et al. reported a reduction of total variability, considered a marker
of the capability of the cardiovascular system to respond to stress-
ors (Zhong et al., 2005) as well as an important change of the
sympatho-vagal balance towards a sympathetic predominance. In
fact, the analysis of HRV showed that acute sleep loss was able
to induce an enhanced sympathetic modulation, as shown by the
increased of the LF component and the LF/HF ratio, and a reduction
of vagal control, expressed by lower values of the HF component
 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
(Sauvet et al., 2014; Zhong et al., 2005). Using a different acute SD
model, we observed that this resting sympathetic excitation was
also associated to blunted responses to head-up tilting (Tobaldini
et al., 2013a,b). Moreover, we also reported an increased leuko-
cyte release of IFN-␥ following acute SD, independent by changes
in hypothalamic-pituitary axis (Tobaldini et al., 2013a,b).
Thus, acute SD has important effects on heamodonymic and
autonomic parameters and also on inflammatory responses. SD
causes the increased production of pro-inflammatory plasma
cytokines (such as IL-21, IL-1, TNF-␣, PCR and IFN-␥), an
endothelial-dependent vasodilatation and an alteration of adhe-
sion molecule function (Irwin et al., 2008; Meier-Ewert et al., 2004;
Sauvet et al., 2014; Tobaldini et al., 2013a,b). Recently, two papers
showed that after one week of partial sleep restriction (4 h of
sleep per night) endothelial-dependent vasodilatation was reduced
independently of autonomic profile but associated with a strong
activation of the inflammatory and metabolic pathways (Sauvet
et al., 2015; Calvin et al., 2014).
Experimental studies on the effects of chronic SD in healthy sub-
jects showed analogous results. In fact, after five days of partial
sleep loss, autonomic profile dramatically changed with a reduc-
tion of total HRV and a shift of the sympatho-vagal balance towards
a sympathetic predominance and a parasympathetic withdrawal
(Takase et al., 2004; Dettoni et al., 2012). However, few studies
found opposite results with no changes in the autonomic profile
induced by chronic SD (Muenter et al., 2000). In this setting, it
is important to underline that chronic SD studies are more dif-
ficult to perform compared to the acute ones. The studies differ
in terms of experimental settings (attended laboratory conditions
vs. real life models), in terms of experimental timetables (such as
hours of sleep deprivation per day and total protocol duration),
and in terms of study population characteristics (Takase et al.,
2004; Dettoni et al., 2012; Muenter et al., 2000; Tobaldini et al.,
2013a,b).
These limits render the results of these studies not homo-
geneous and, definitely, future controlled studies are needed to
clarify the detrimental effects of chronic SD in healthy subjects.
Recently, Sauvet and colleagues showed that after one week of par-
tial sleep restriction (4 h of sleep per night), endothelial-dependent
vasodilatation was reduced independently of autonomic profile
but associated with a strong activation of the inflammatory and
metabolic pathways (Sauvet et al., 2015).
In summary, based on the published evidences, we can state
that acute sleep loss is able to modify heamodynamic control and
autonomic cardiovascular regulation in healthy subjects, together
with an altered inflammatory response and endothelial function.
Data on the effects on these biological pathways induced by chronic
restriction are weak and future and ad hoc studies are required to
shed a new light on this essential topic.
4. Pathological sleep deprivation
As stated before, pathological SD can be the consequence of sev-
eral sleep disorders. In this review, we will focus on three main
categories of sleep disturbances: sleep disordered-breathing (SDB),
such as obstructive sleep apnea syndrome (OSA), insomnia and
neurological disorders such as PLM and RLS. In fact, although the
pathophysiological differences, one of the most important com-
mon element of these sleep disorders is the condition of chronic
SD, which has a complex series of biological consequences.
From an epidemiological point of view, it has been shown that
a short sleep duration is associated with coronary artery disease
and myocardial infarction, cerebrovascular events, diabetes and
obesity, after adjustment for socioeconomic and demographic risk
factors and comorbidities (Grandner et al., 2012). The prevalence
323
of OSA in the general adult population is approximately 24% in
men and 9% in women and these percentages doubled from the
last decade, when obesity has been identified as an important
risk factor. In addition, patients with cardiovascular diseases do
have a higher prevalence of OSA, which is present in 30- 80%
of patients with arterial hypertension, 30–60% of patients with
chronic coronary artery diseases and 50–80% of patients with con-
gestive heart failure (Stopford et al., 2013). A recent systematic
review on the risk of adverse cardiovascular outcomes in patients
with OSA showed a relation between the presence of OSA and
all cause mortality and a composite cardiovascular outcomes (i.e.
stroke, congestive heart failure, myocardial infarction) in men,
while in women this relation was attenuated (Kendzerska et al.,
2014). In addition, the apnea/hypopnea index (AHI), an index that
sum the amount of apneic and hypopneic events during the sleep
period, was the only independent predictor of adverse events
(Kendzerska et al., 2014). However, the association between OSA
and diabetes did not reach a statistical significance after the adjust-
ment for confounding factors such as age, sex and body mass index
(Reichmuth et al., 2005). The pathophysiological cascade leading
from OSA to cardiovascular events has been extensively described
(Narkiewicz and Somers, 1997; Kasai et al., 2012; Shamsuzzaman
et al. 2002).
In general, the upper airways collapse several times per
hours inducing the occurrance of microarousals and a fragmen-
tation of the physiological sleep. Second, during each apneic
episode, hypoxia-hypercapnia followed by reoxigenation occur,
thus altering the physiological blood gases exchange. Chemore-
flex activation is associated with the occurrence of EEG alterations
(microarousals); each inspiration effort against the occluded upper
airways induces an increase in negative intrathoracic pressure
(Muller manoeuvre) with important consequences on the heart
anatomy, such as atria enlargement and remodelling and stretch
of the pulmonary vein (PV) ostia (Caples and Somers, 2009). All
these three acute components of obstructive apneas lead to the
activation of several different biological pathways. One of the most
important is the deregulation of the ANS, with repetitive bursts of
sympathetic activity induced by the activation of chemoreflexes
and continuous sympathetic and parasympathetic coactivation
during apneas (Paton et al., 2006). This sympathovagal coactiva-
tion is a hallmark of OSA and it can be a key factor in triggering
major life-threatening arrhythmias in these patients. In addition, a
series of intermediate mechanisms are activated by apneic events,
such as oxidative stress, systemic inflammatory response, platelet
activation and aggregation, endothelial dysfunction and metabolic
alterations (Dewan et al., 2015).
While the link between OSA and cardiovascular disorders has
been extensively addressed by the literature, the relationship
between neurological disorders and sleep deprivation, as due to
insomnia or RLS and PLM, is still elusive. Insomnia, which is
defined as a subjective difficulty in initiating and/or maintaining
sleep or a sensation of non-restorative sleep affects approximately
10–15% of general population (Murphy and Peterson, 2015). Grow-
ing evidence suggests that patients with insomnia have a higher
prevalence of hypertension (Vgontzas, 2009) congestive heart fail-
ure (Hayes et al., 2009), and coronary artery disease. Recently, a
prospective study in men (Li et al., 2014a,b) supported the hypoth-
esis that insomnia symptoms were associated with an increased
risk of cardiovascular mortality, mostly in men with difficulty in
initiating sleep.
Finally, similar data have been reported regarding the asso-
ciation between RLS and PLM with cardiovascular diseases. Few
data are available, and although some evidences suggest that these
patients are at increased risk of developing hypertension, heart
disease and stroke, the studies are contrasting and not conclusive
(Walters and Rye, 2009).
324 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
4.1. Pathological sleep deprivation and congestive heart failure
Congestive Heart Failure (CHF) is a pathological condition char-
acterized by the inability of the heart to fulfil the oxygen demand
of the periphery. CHF can be due to a systolic dysfunction, i.e. an
impairment of the ability of the ventricles to contract properly or
to an increased stiffness of the ventricular walls during diastolic
phase.
SDB must be considered a very important comorbidity in
patients with CHF. In fact, SDB has a high prevalence, affecting more
than 50% of the CHF patients with systolic heart failure (Schulz et al.,
2007) and also in patients with CHF with preserved ejection fraction
(Herrscher et al., 2011).
Gottlieb and colleagues showed that the presence of OSA
increases the risk of new onset CHF in men (hazard ratio 1.13, 95%
CI 1.02–1.26) per 10-unit increase in apnea-hypopnea index (AHI,
the number of episodes of apneas and hypopneas per hour of sleep).
Men with a severe OSA (AHI > 30) are 58% more likely to develop
CHF compared to non-OSA subjects (Gottlieb et al., 2010). Patients
with CHF are at higher risk of developing central sleep apnea and
periodic breathing (Cheyne-Stoke respiration), a particular condi-
tion characterized by breathing that becomes progressively deeper
and faster followed by a gradual slowing of the breathing followed
by an apnea (Lanfranchi et al., 1999; Bradley and Floras, 2003a,b).
Interestingly, central sleep apnea is an independent risk of
adverse outcome in heart failure patients (La Rovere et al., 2007;
Lanfranchi et al., 1999), and also more severe the central sleep
apnea, higher the probability to develop clinical symptoms and
signs of heart failure and to develop decompensated heart failure
in older men (Javaheri et al., 2016). It has been also shown that
central sleep apnea (CSA) is an independent risk factor that predict
hospital six months readmission (Khayat et al., 2012). OSA And CSA
are often coexisting in CHF patients.
The strong link between OSA and CHF have important con-
sequences on long-term outcomes in these patients. In fact, CHF
patients with a comorbid moderate-severe untreated OSA dou-
ble the all-cause mortality compared to CHF patients without OSA
(Levy et al., 2002) and OSA is a strong independent risk of mortality
in these patients (Wang et al., 2007). CHF is characterized by a pro-
gressive loss of sympathetic rhythmical oscillation associated with
an increased firing rate of sympathetic discharge. The progressive
loss of oscillatory properties of sympathetic outflow is accompa-
nied by a consensual reduction in HRV, supporting the hypothesis
of a cardiac system less able to respond adaptively to stressors
stimuli (Guzzetti et al., 2001). In addition to this autonomic dereg-
ulation, CHF patients with comorbid OSA not only have repetitive
bursts of sympathetic activity during apneas due to the activation
of chemoreflexes (Narkiewicz et al., 1998a,b) but also an increased
vagal activity due to hypoxia and upper airway obstruction. This
phenomenon causes a reflex bradycardia, which is then followed
by a post-event sympathoexcitation (Mehra and Redline, 2014).
This autonomic coactivation, together with pulmonary vasocon-
striction induced by hypoxia, right ventricular hypertension and
acute stretch of the atria wall and pulmonary vein stretch could
trigger the onset of arrhythmias in CHF patients, especially atrial
fibrillation (Mehra and Redline, 2014; Romero-Corral et al., 2007).
Considering the detrimental effects of this combined sympathetic
and vagal activation in patients with both CHF and OSA, a growing
interest has been focused on the possible beneficial effects of OSA
treatment in these patients in terms of mortality. So far, the optimal
therapy for OSA is the use of continuous positive airways pressure
(CPAP), which is able to reduce symptoms and improve quality of
life and to significantly reduce the incidence of fatal and non fatal
cardiovascular events (Marin et al., 2005).
However, the CPAP treatment effectiveness in CHF patients is
still debated. It has been reported that one-to-three months of
CPAP in CHF patients with OSA was able to improve left ventric-
ular ejection fraction, NHYA class and to reduce heart rate and
blood pressure (Mansfield et al., 2004). In line with these results,
the CANPAP study observed that CPAP was able to reduce the num-
ber of obstructive apneas, to improve nocturnal oxygenation and to
increase the left ventricular ejection fraction, but without affecting
survival rate (Bradley et al., 2005). A very recent randomized clinical
trial focused on the use of a specific ventilation, the adaptive servo-
ventilation (ASV) in CHF patients with reduced ejection fraction and
central apneas, failed to reach its primary endpoints (i.e. reduction
of death for any cause, cardiovascular intervention and worsen-
ing heart failure). On the contrary, and quite unexpectedly, results
showed that all-cause and cardiovascular mortality were higher
in the ASV group compared to the medical therapy group (hazard
ratio, HR, for death for any cause 1.28, 95%CI 1.06–1.55, p = 001; HR
for cardiovascular death 1.34, 95% CI 1.09–1.65, p = 0.006) (Cowie
et al., 2015). Therefore, there is still lack of evidence from random-
ized clinical trials that the reduction in obstructive as well as central
apneas in HF patient is associated with a reduction in morbidity and
mortality.
While a large amount of studies have been performed on the epi-
demiological, physiopathological and clinical consequences of the
association between OSA and CHF, very few studies have addressed
the relationship between insomnia and CHF. What is well known is
that insomnia has a high prevalence in CHF, with insomnia symp-
toms present in a variable percentage between 23 and 73% (Hayes
et al., 2009). It has been recently shown that in subject initially free
from CHF, insomnia symptoms were associated with an increased
incidence of CHF development during a 10 years follow-up in a
dose-dependent manner (Laugsand et al., 2014).
4.2. Pathological sleep deprivation and hypertension
Since 2003, OSA has been considered as the first identifiable
cause of hypertension (Mancia et al., 2014). The prevalence of
moderate-to-severe OSA in patients with primary hypertension is
approximately 30%, while 80% in patients with resistant hyper-
tension (Pedrosa et al., 2011; Floras, 2015), therefore the link
is clinically relevant. The last European Society of Hypertension
guidelines strongly recommend the OSA screening for all patients
with resistant hypertension. Again, alterations in cardiovascular
autonomic control play a relevant role. The ANS control is altered
not only during night-time, with a continuous waxing and waining
of sympathetic bursts during apneic events, but also during day-
time, with a constant predominance of sympathetic modulation to
the sinus node and the vessels (Narkiewicz et al., 1998a,b; Konecny
et al., 2014).
However, although the association between hypertension and
OSA has been well established from a pathophysiological and an
epidemiological point of view, the causal role of OSA in hyperten-
sion is a still debated issue. In fact, several seminal papers reported
that untreated OSA increased the risk of developing hypertension
(HR for incident hypertension in untreated OSA patients of 1.96
(95% CI 1.44–2.66)) (Marin et al., 2012). However, other studies
did not confirm these results after adjusting them for confounding
variables such as age, sex, body mass index, tobacco use and neck
circumference (Durán-Cantolla et al., 2011). This contrasting data
can be related to the huge overlap of the risk factors for OSA and
hypertension, first of all the relation with obesity.
Interesting but contrasting results have been published on the
effects of CPAP treatment on hypertension. A Cochrane’s sytem-
atic review published in 2006 underlined that CPAP is effective on
sleepiness symptoms and quality of life measures in subjects with
moderate and severe OSA, being more effective than oral appli-
ances in reducing respiratory disturbances. Data on short term trials
 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
showed that CPAP lowers ABP but long-term data are required for
all outcomes (Giles et al., 2006).
A very recent meta-analysis published by Liu and colleagues
showed that the pooled changes after CPAP treatment for 24-h
ambulatory systolic and diastolic blood pressure were −4.78 mmHg
(95% confidence interval [CI], −7.95 to −1.61) and −2.95 mmHg
(95% CI, −5.37 to −0.53), suggesting a mild, but significant reduc-
tion in blood pressure with CPAP treatment (Liu, 2016). Thus,
while CPAP is able to reduce cardiovascular mortality, it is unclear
whether this effect is related to the reduction of single cardiovascu-
lar risk factor such as hypertension, or, more likely, to a synergistic
effect on the several intermediate mechanisms aforementioned.
An increasing number of reports is supporting the hypothesis
that also insomnia is a potential risk factor for arterial hyperten-
sion. A longitudinal study reported that, compared to subjects with
normal sleep, subjects who slept less than 5 h per night due to
insomnia had the highest risk of hypertension (OR 5.1, 95% CI 2.2,
11.8), followed by the group who slept 5–6 h per night (OR 3.5,
95% CI 1.6, 7.9). The authors concluded that insomnia with short
sleep duration was associated with an enhanced risk of developing
hypertension, similarly to SDB (Vgontzas et al., 2009a,b). Causal
mechanisms involved in this relationship are still under scrutiny.
It has been hypothesiszed that a hyperarousal state induced by
insomnia would be instrumental for the development of hyper-
tension (Bonnet and Arand, 2010; Li et al., 2015). Another major
problem in determining the relevance of insomnia in hypertension
is the high prevalence of depression in insomniacs (Buysse et al.,
2008; Pillai et al., 2016).
Finally, the effects of PLM and RLS with hypertension found
inconclusive results. PLM seem to be associated with daytime
hypertension and patients with daytime hypertension have a
greater number of PLMS. However, a causative role is very hard
to be established at this moment.
Inconsistent data have been published also on the relation
between RLS and hypertension: while Hogl and colleagues found no
relationship between these two conditions in a community study of
prevalence (Högl et al., 2005), a positive association between RLS
and hypertension has been found in other studies (Ulfberg et al.,
2001). Thus, the inconsistency of the data suggest the need for
further ad hoc investigations.
4.3. Pathological sleep deprivation and coronary artery disease
Epidemiological studies showed that approximately 50% of
patients with Coronary Artery Diseases (CAD) have moderate to
severe OSA (Peker et al., 1999) and one half of the patients admitted
to hospitals for a ST-elevation myocardial infarction have an undi-
agnosed severe OSA (Lee et al., 2011). Prevalence of OSA is higher in
patients with reduced ejection fraction than with preserved ejec-
tion fraction (Arzt et al., 2015).
In addition, an important gender difference has been noticed:
OSA is a risk factor for CAD in men but this result has not been
confirmed in women (Arzt et al., 2015).
From a physiopathological point of view, in addition to hypoxia,
disruption of physiological sleep and autonomic deregulation with
bursts of sympathetic over activity, the repetitive episodes of upper
airways collapse lead to the uncoupling of myocardial workload
and coronary blood flow.
In fact, blood flow increases after each apneic event but with a
certain delay with respect to the increase in myocardial workload
(Hamilton et al., 2009). This phenomenon could be responsible for
the strong link between OSA and ischemic events in subjects with
CAD. It is worth noting that few evidences suggested that patients
with chronic CAD and OSA have more coronary collaterals than
patients without OSA, suggesting that OSA has a possible protec-
tive role, possibly related to the production of vascular endothelial
325
growth factors induced by intermittent hypoxia (Steiner et al.,
2010), although the clinical relevance of this phenomenon is still
debated. The comorbidity of OSA also impacts on the clinical pro-
gression of the myocardial infarction. In the early phases of acute
myocardial infarction, in OSA patients heart is more sensitive to the
increased intrathoracic negative pressure induced by apneas, thus
leading to a worse recovery from acute events (Arzt et al., 2015). In
addition, OSA patients tend to have prolonged myocardial ischemia,
altered ventricular remodelling and lower ventricular function
(Arzt et al., 2015; Nakashima et al., 2006). The effects on long term
outcomes have been widely investigated. In a prospective study,
Gottlieb and colleagues demonstrated that OSA is a significant risk
factor for the incidence of an acute CAD, such as acute myocar-
dial infarction, revascularization procedure, and death for cardiac
causes, after the adjustment for multiple risk factors (adjusted haz-
ard ratio 1.10, 95%CI 1–1.12 per 10-unit increase in AHI) in men
under 70 s (Gottlieb et al., 2010). This result was not confirmed in
women and in older men (Gottlieb et al., 2010). It has been also
shown that the event free survival rates was worse in the severe
OSA group than that in the non severe OSA (p = 0.021) (Lee et al.,
2011) and patients with known CAD or previous myocardial injury
with OSA comorbidity have a greater all cause mortality.
Therefore, these results showed that OSA has a high prevalence
in patients with CAD and that OSA is a significant independent risk
factor for the development of ischemic heart disease. In addition,
patients with CAD and a comorbid OSA have a worse short term
and long-term outcomes. Therefore, the prompt identification of
CAD patients with OSA comorbidity is essential to identify high-risk
patients and to tailor ad hoc diagnostic and therapeutic strategies
in these patients.
As to SD induced by insomnia, a population-based study showed
that difficulties initiating sleep were associated with deaths for CAD
in males [RR 3.1; 95%, CI, 1.5–6.3; P < 0.01], but not in females, after
the adjustment for the most important risk factors. However, short
sleep duration was independent from the risk of CAD or total mor-
tality, suggesting a relationship between troubles falling asleep and
mortality for CAD in males (Mallon et al., 2002). However, con-
clusive results on the effects of sleep loss secondary to insomnia
and CAD are still debated and additional large population based
studies are required. However, Laungsand et al. (Laungsand et al.,
2011) in a prospective study observed a dose dependent associ-
ation between the symptoms of insomnia and acute myocardial
infarction (AMI) risk. Namely, the multiadjusted hazard ratios for
AMI was 1.45 (95% confidence interval 1.18–1.80) for people with
difficulties initiating sleep. This study was accompanied by an edi-
torial suggesting that, so far, we have enough evidence to consider
sleep as one of the ten modifiable cardiovascular risk factor (Redline
and Foody, 2011). Recently, a further prospective study in men con-
firmed that insomnia symptoms were associated with an increased
risk of cardiovascular mortality (Li et al., 2014a,b).
As to the relation between RSL and CAD, primary RLS did not
have a higher risk of developing CAD compared to a cohort study
(HR = 0.99; 95% CI = 0.89–1.13) while secondary RLS was associated
with an increased risk of CAD (HR = 1.40; 95% CI = 1.25–1.56) (Van
Den Eeden et al., 2015).
4.4. Pathological sleep deprivation and atrial fibrillation
A large amount of literature has been published on the detri-
mental consequences of patological sleep deprivation induced by
OSA and atrial fibrillation (AF), not only regarding the increased
risk of developing AF for OSA patients and higher incidence of
recurrence but also long term outcomes. In addition to the detri-
mental effects induced by the hypoxia—reoxigenation episodes
during apneas, a major role might be played by the coactivation
of the ANS during hypoxiemic episodes. Vagal activation would
326 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
Fig. 2. Obstuctive sleep apnea (OSA) is one of the most common sleep disordered breathing. OSA is characterized by repetitive episodes of upper airways collapse, which
lead to sleep fragmentation, alteration of blood gases exchange and significant changes in intrathoracic pressures. These mechanisms, through an important autonomic
derangment and changes in cardiac anatomy, are responsible for an increase risk of atrial fibrillation in OSA patients.
induce an impaired refractoriness of the cardiac conducting system,
creating an electrogenic background for triggering AF. Moreover,
apneic events induce changes in intrathoracic pressures causing
atria enlargment and tissue stretch and remodeling at the pul-
monary vein ostia, leading to a “mechanical” trigger for AF onset
(Caples and Somers, 2009) [see Fig. 2].
Interestingly, not only OSA has been shown to be a clear risk
factor for the incidence of AF but also OSA has a higher prevalence
in AF patients compared to the general population (49% versus 32%,
P = 0.0004), with an adjusted odds ratio for the association between
AF and OSA of 2.19 (P = 0.0006) (Gami et al., 2004). Interesting data
have been published on the effects of OSA treatment on AF. A very
recent meta-analysis showed that OSA patients treated with CPAP
had a 42% decreased risk of AF, with benefits of CPAP more evident
for younger, obese, and male patients (p < 0.05). On the contrary, an
inverse relation has been established between CPAP therapy and AF
recurrence (Qureshi et al., 2015). Two recent papers showed that
patients under CPAP therapy had a higher AF-free survival rate
(71.9% vs. 36.7%; p = 0.01) and AF-free survival of antiarrhythmic
drugs compared to OSA patients without CPAP treatments. Patients
with OSA had a greater risk of AF recurrence after catheter abla-
tion compared to patients without OSA and a higher risk to repeat
ablation following pulmonary vein isolation (PVI). On the contrary,
OSA patients under CPAP had a risk of AF recurrence analogous
to that of patients without OSA and the efficacy of catheter abla-
tion for AF was similar between patients without OSA and patients
with OSA undergoing CPAP treatment (Li et al., 2014a,b; Fein et al.,
2013).
Thus, these data suggest that the relationship between OSA and
AF is bidirectional, with OSA patients at higher risk to develop AF
and AF patients with a greater prevalence of OSA. The efficay of AF
tratment is affected by the presence of OSA and an effective OSA
treatment with CPAP improve AF outcomes (Ng et al., 2011). There-
fore, a prompt identification of OSA in AF patients and adequate
therapeutic options should be considered in order to significantly
improve the long-term outcomes in these patients.
4.5. Pathological sleep deprivation and metabolic diseases
Type 2 diabetes mellitus (T2 DM) is a major public health
problem, which affects approximately 8% of the United States pop-
ulation, with an incidence that has doubled over the last 30 years
(American Diabetes Association, 2010).
In general, both short sleep duration (6 h or less) and long sleep
duration (9 h or more) are associated with increased prevalence of
T2 DM and impaired glucose tolerance, even in absence of evident
signs of insomnia (Gottlieb et al., 2005). Sleep loss associated with
hyperactivation of sympathetic nervous system and intermittent
hypoxia in OSA patients leads to oxidative stress, inflammation,
adipokines changes and insuline resistance, which predispose to
an increased risk of T2 DM development.
Tasali et al. (2008a,b) have elegantly demonstrated that, all-
night selective suppression of slow wave sleep (SWS), without any
change in total sleep time, results in a marked decrease in insulin
sensitivity without an adequate compensatory increase in insulin
release. This leads to reduced glucose tolerance and increased dia-
betes risk. Importantly, the magnitude of the decrease in insulin
sensitivity was strongly correlated with the magnitude of the
reduction in SWS. Moreover, loss of slow wave sleep was associ-
ated with a shift of the nighttime sympathovagal balance towards
a sympathetic predominance. These findings suggested a clear role
for SWS in the maintenance of normal glucose homeostasis likely
through ANS modulation (Tasali et al., 2008a,b; Dijk, 2008).
Several epidemiological studies have suggested that OSA is an
independent risk factor for the development of T2DM and more
severe OSA, higher the probability of a worse glycemic control
and of T2 DM incidence (Kent et al., 2014). For instance, a large
epidemiological study demonstrated that mild or moderate-to-
severe OSA patients had odds ratio of 1.27 and 1.46 for impaired
glucose tolerance compared with non OSA subjects after the adjust-
ment for multiple potential confounding factors and the severity
of nocturnal hypoxemia was independently associated with glu-
cose intolerance (Punjabi et al., 2004). In addition, the percentage
of HbA1c, which is a marker of long-term glucose control in dia-
 E. Tobaldini et al. / Neuroscience and Biobehavioral Reviews 74 (2017) 321–329
betic individuals, was positively correlated with the severity of OSA
(Aronsohn et al., 2010).
The optimal treatment with CPAP has been shown to be effective
on glycemic control in T2 DM. Several evidences showed significant
improvements in insulin sensitivity in patients with OSA who are
treated with CPAP (Babu et al., 2005); however, while a random-
ized clinical study demonstrated an incremental improvement in
insulin sensitivity index for each additional hour of nightly CPAP
use, other evidence suggested significant improvements in insulin
sensitivity only in severe OSA patients (Weinstock et al., 2012).
In addition to SDB, also sleep loss due to insomnia was associated
with a higher risk for diabetes. Objective sleep duration may predict
cardiometabolic morbidity of chronic insomnia, independently of
age, gender, race, smoking, obesity, diabetes, alchool consumption,
depression and the presence of SDB (Vgontzas et al., 2009a,b). The
highest risk of diabetes was in subjects with insomnia and less than
5 h of sleep (odds ratio [95% CI] 2.95 [1.2–7.0]) and in insomniacs
who slept 5–6 h per night (odds ratio 2.07 [95% CI 0.68–6.4]) com-
pared with the normal sleeping of more than 6 h (Vgontzas et al.,
2009a,b)
On the association between RLS and diabetes, the prevalence
of RLS was 28.6% in diabetes and 7.1% in control group (P = 0.001),
without sex differences (Zobeiri and Shokoohi, 2014), suggesting
a significant association between RLS and diabetes which must be
taking into account in evaluating the potential detrimental effects
of RLS in diabetic patients.
5. Conclusions and perspectives
SD is a growing health problem in the whole world. This con-
dition is related to changes in lifestyle habits and an increased
prevalence of sleep disorders, such as insomnia and OSA. Inde-
pendently of its primary cause, SD can impinge upon several
biological pathways, such as cardiovascular autonomic control,
oxidative stress, inflammatory responses and endothelial function.
All these pathophysiological mechanisms are resposible for the link
between SD and increased risk of cardiovascular diseases, such as
hypertension, congestive heart failure, coronary artery disease and
arrhythmias, and metabolic disorders (diabetes and obesity).
Thus, an early diagnosis of subjects with SD is essential in order
to reduce the risk of cardiovascular and metabolic diseases in gen-
eral population.
Future large population studies are needed in order to evaluate
how much impact the effects of SD treatment have on cardiovas-
cular and metabolic diseases.
Acknowledgments
This work was partly supported by a European Regional Devel-
opment Fund—Project FNUSA-ICRC (No. CZ.1.05/1.1.00/02.0123) to
N.M
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