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.