Obstructive sleep apnea (OSA) is a common sleep disorder and its prevalence increases with age and obesity (1). A recent study reported a 23.4 and 49.7% prevalence of moderate-to-severe OSA in females and males, respectively (2). Multiple studies have demonstrated an association between OSA and cardiovascular diseases, particularly hypertension. The Sleep Heart Health study reported a prevalence of 59, 62, and 67% for hypertension in mild, moderate, and severe OSA, respectively (3). Meanwhile, OSA is particularly common in refractory hypertension (4, 5). Studies have also demonstrated an independent relationship between OSA severity and blood pressure. A large cross-sectional study demonstrated that, after adjusting for age, body mass index (BMI), and gender, OSA severity index was a significant predictor of both systolic (SBP) and diastolic (DBP) blood pressures, and each additional apneic event per hour of sleep increased the odds of hypertension by about 1% (6). A linear increase in SBP and DBP with increasing OSA severity was also demonstrated after adjusting for age, BMI, and gender (7).

Obstructive sleep apnea is characterized by two cardinal pathophysiological features, including intermittent hypoxia (IH) and sleep fragmentation (SF). IH has long been recognized as one of the mechanisms in the development of OSA-related hypertension, and rodent studies have demonstrated a robust association between IH and hypertension (8). It has been suggested that IH may increase the sympathetic nervous system and renin-angiotensin system activity, (9–11) cause endothelial dysfunction, (12, 13) and contribute to inflammation and metabolic disorders (14, 15) to induce hypertension. Recent evidence also implicates SF as a distinct trigger for elevated blood pressure. Rodent studies have demonstrated that SF contributes to sympathetic activation and endothelial dysfunction, which promotes the development of hypertension (16). However, the results of clinical studies have been inconsistent. Some studies have demonstrated a positive association between SF and the risk for hypertension, (17–19) while others have found no effects of SF on blood pressure (20–22). Most of these clinical studies had some limitations, including small sample sizes (19–21) or focusing on specific populations (17, 18). And whether the risk of hypertension increases with the elevating severity of IH/SF is not yet known. In addition, the interaction between IH and SF in the association with blood pressure has not been evaluated.

We performed this study to address these gaps. We aimed to deeply assess the independent associations of the two cardinal features of OSA, IH and SF, with blood pressure, and the effects of the interaction between IH and SF.

We found that after adjusting for multiple variables, compared with subjects with lower ODI quartiles, those with higher ODI quartiles had significant higher SBP and DBP. Logistic regression analyses showed that compared with subjects with lower ODI quartiles, those with higher ODI quartiles were more likely to have abnormal DBP and hypertension after adjusting for multiple variables. Similarly, compared with subjects with lower MAI quartiles, those with higher MAI quartiles had significant higher SBP and DBP, and were more likely to have abnormal DBP and hypertension. Furthermore, no significant multiplicative interaction of ODI and MAI on blood pressure was detected.

In this study, we found that those with more severe IH (represented by ODI) had significant higher SBP and DBP, and were more likely to have abnormal DBP and hypertension than those with less severe IH. An increasing number of studies have demonstrated that IH can induce hypertension. In human experimental models, hypoxia has been shown to lead to measurable elevations in blood pressure and sympathetic activation (25–28). IH can stimulate the chemoreceptors and carotid body, and attenuate the activation of carotid baroreceptor, resulting in increased sympathetic activation (29, 30). Persistent sympathetic activation not only elevates blood pressure by increasing vascular resistance and vascular remodeling but also causes sodium retention, impaired natriuresis, and blood pressure elevation by activating the renin-angiotensin system. Meanwhile, IH can promote endothelial dysfunction, systematic inflammation, and metabolic dysfunction, including dyslipidemia and glucose metabolism disorder, which contributes to the development of hypertension (31).

Results from previous clinical studies about the relationship between SF and blood pressure have been controversial. The PROOF-SYNAPSE study of 780 healthy older subjects found that repetitive sympathetic arousals during sleep were associated with elevated SBP and a higher risk of hypertension (17). (18) found that arousal index was an independent risk factor for DBP in male patients (18). (19) demonstrated that arousal index independently predicted a small percentage of the variance in nocturnal reduction in DBP (19). However, other studies have failed to demonstrate an independent relationship between SF and blood pressure. A study of 1021 subjects showed no independent association between SF and awake blood pressure after controlling for the influence of AHI in subjects with AHI ≥ 1. Two other studies also demonstrated that SF was not independently associated with blood pressure (20, 21). In our study, we found that those with more severe SF (represented by MAI) had significant higher SBP and DBP, and were more likely to have abnormal DBP and hypertension than those with less severe SF. A rodent study has demonstrated that long-term SF induces vascular endothelial dysfunction and mild blood pressure increase, (16) and leads to morphologic vessel changes characterized by elastic fiber disruption and disorganization, increased recruitment of inflammatory cells, and altered expression of senescence markers. This suggests a role for SF in the cardiovascular morbidity related to OSA, including hypertension (16).

In addition to the independent relationships between IH/SF and blood pressure, we also explored the multiplicative effects of IH and SF on blood pressure, and found no evidence of an interaction. This suggests that these two factors contribute independently to abnormal blood pressure.

Meanwhile, we explored the relationships between BMI and hypertension. We found those with higher BMI quartiles were more likely to have abnormal SBP and hypertension than those with lower BMI quartiles, which indicated the important role of obesity in hypertension (Supplementary Table 1). We also detected the interactions between BMI and ODI on abnormal blood pressure, and found no significant interactions (Supplementary Table 2). Furthermore, we divided the subjects into two categories according to the median BMI, and found that only in BMI > 26.37 category, those with higher MAI quartiles were more likely to have abnormal DBP, which needed to be further studied in future (Supplementary Table 3).

This study had some limitations. First, it was a retrospective study, so causality cannot be inferred. Second, the statistical power was relatively low due to the small sample size. Third, although we adjusted for several common confounding factors, other more complex factors, such as lifestyle and exercise, were not taken into consideration. Despite these limitations, the sleep data based on standard PSG and objective measurements increased the credibility of our results.

In conclusion, we found that subjects with more severe IH or SF had significant higher SBP and DBP, and were more likely to have abnormal DBP and hypertension than those with less severe IH or SF. There was no multiplicative interaction between IH and SF regarding the effects on blood pressure. Therefore, it is important to consider the roles of both SF and IH while treating hypertensive patients with OSA.

The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.

This study was approved by the Internal Review Board of the Institutional Ethics Committee of the First Affiliated Hospital of Nanchang University (Approval No. 2020-12-139), and the study was conducted in accordance with all relevant tenets of the Declaration of Helsinki. This was a retrospective study. The ethics committee waived the requirement of written informed consent for participation.

YYX and YPX designed the study and wrote and manuscript. KY and YYX collected the data. KY performed the analysis. All authors contributed to the article and approved the submitted version.

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

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