Discussion
Obstructive sleep apnoea (OSA) consists of repeated episodes of
extrathoracic upper airway obstruction associated with intra-arterial
hypoxaemia and hypercapnia (17). OSA, as a chronic condition is also
responsible for endothelial dysfunction, with early atherosclerosis
plaque evidence, and rapid increase of cardiovascular risk (6). Since,
even very recently, several studies have pointed out the role of the
degree of OSA, as factor likely responsible for increasing
cardiovascular risk (18), on the other hand, by the contrast, recent
evidences, derived by the results of an observational 1 year study, did
not establish any correlation between severe obstructive sleep apnea
syndrome and increased cardiovascular risk, as well as augmented
cardiovascular co-morbidities (19). This debate has involved, over time,
several investigators, who hypothesized both possible scenarios. Thus,
it remains under discussion the primary role of OSA for developing
increased cardiovascular risk in these subjects (20).
A validate assessment established that the metabolic syndrome commonly
coexist with OSA, and obesity is perhaps the strongest predictor of OSA
with 40–60% of obese subjects suffering from sleep disorders breathing
(21). The burden of obesity is worrisome; the obesity prevalence is
globally increasing, affecting 10 to 25 % of the world population and
is associated with a wide range of abnormalities, including elevated
systemic as well as elevated pulmonary artery pressures (22), both
sustained by systemic inflammation (7,10). Furthermore, obesity is
characterized by increased production and secretion of a wide range of
inflammatory molecules, including TNF-alpha and interleukin-6, which
have both, local effects on adipose tissue physiology, and systemic
effects on other organs, such as the cardiovascular system (12). Thus,
contributing to activate various inflammatory cells, such as lymphocytes
and monocytes, leading to over-expression of pro-inflammatory mediators,
that may establish irreversible endothelial dysfunction. The latter
observation has been recently demonstrated in a rabbit model (23).
In the present study, we found In the whole OSA population, the
percentage of cardiovascular risk was weakly related with BMI (r=0.33;
P<0.001) but not with AHI.
AHI values were higher in obese (43.3±1.3) than in lean (34.8±3.1) and
overweight subjects (35.5±1.8, P<0.01 ANOVA). Overall, a
direct relationship was evident between AHI and BMI. When AHI values
were stratified in tertiles, the percentage cardiovascular risk did not
vary with increasing AHI values.
Then, we assumed that the degree of OSA per se does not significantly
increase the cardiovascular risk, while the coexistence with a higher
BMI, might be likely responsible for the worsen of the prognosis.
In two recent studies (24, 25), endothelial peripheral dysfunction in
OSA patients has been significantly found in mild OSA and in minimally
symptomatic OSA. The endothelial dysfunction decreased by 3 months of
C-PAP treatment. Indeed, in our study, we demonstrated that moderate or
severe OSA patients show a progressive brachial endothelial dysfunction,
established by flow-mediated dilation (FMD) assay. The most evident
finding was the significant reversibility of FMD in the group of
patients treated with C-PAP therapy, for at least 3 months (24).
In addition, OSA-associated chronic intermittent hypoxia (CIH), in
obesity, may complicate adipose tissue hypoxia with over-production of
adipose tissue inflammation, by increasing macrophage infiltration and
activating redox-sensitive transcription factors, as well as, ER stress
signaling proteins (26). In a very recent study, it has been evaluated
the effect of OSA and C-PAP on changes in adipose tissue
inflammatory/hypoxia markers, there assessed by testing mRNA levels of
genes related to macrophage infiltration, hypoxia, and ER stress (27).
In this investigation, authors performed abdominal subcutaneous adipose
tissue biopsies from OSA and non-OSA obese (BMI > 35)
individuals, at baseline and after 24 weeks (T1) of weight-loss
intervention plus continuous positive airway pressure (C-PAP), or
weight-loss intervention alone, respectively. In obese individuals with
OSA, the reduction of CIH, by a correct C-PAP therapy, associated with a
weight-loss intervention strategy, decreased mRNA expression of markers
related to tissue hypoxia, reduced plasma levels of some
pro-inflammatory cytokines and growth factors, ER stress, inflammation,
and, finally, macrophage infiltration (27),
The endothelial, as well as, the adipose tissue dysfunction, with the
consequent increased cardiovascular risk, are an early phenomenon in OSA
patients, and, according to our results, show-up more severe in subjects
with a BMI higher than 30, while did not appear statistically
significant as compared to the degree of OSA. Thus, the current study
demonstrates that newly diagnosed subjects with OSA are already at risk
for cardiovascular events, and patients with higher levels of BMI, as
well as with higher levels of AHI, experience also the presence of more
elevated number of co-morbidities, as seen by the results of Charlson
Co-morbidities Index (Table 1). In order to avoid this condition, OSA
should be diagnosed as soon as possible, in patients with elevated BMI,
who likely improve their endothelial dysfunction, and subsequently their
cardiovascular risk with C-PAP therapy. This treatment has been shown to
significantly decrease the cardiovascular risk and the development of
several co-morbidities, often responsible for fatal events (24).
This study has several limitations. First, the newly diagnosed
population of OSA was evaluated retrospectively. It is unknown whether
these subjects had a benefit or not by using C-PAP, in terms of
cardiovascular risk, as compared to them who refused or were intolerant.
Second, smoking habit was highly in obese patients, which could play a
significative role for increasing the cardiovascular risk. Third, the
weak association between BMI and AHI and the lack of correlation between
degree of OSA and increased cardiovascular risk was not well
established.
In conclusion, further studies must investigate the pivotal role of
systemic inflammation due to obesity, which appears to be able to
provoke increased cardiovascular risk and augmented co-morbidities, in
OSA patients.