Symptom and comorbidity burden in hypertensive patients with obstructive sleep apnea

Background Obstructive sleep apnea (OSA) is an important but frequently overlooked risk factor for hypertension (HTN). The prevalence of hypertension is high in patients with OSA, but the differences in clinical symptoms and comorbidities between patients with OSA with hypertension and those with normal blood pressure have not been fully defined. Methods This study retrospectively analyzed OSA patients diagnosed for the first time in Lihuili Hospital Affiliated to Ningbo University from 2016 to 2020. Patients were divided into an OSA group with hypertension and an OSA group without hypertension. The sociodemographic information, clinical symptoms, comorbidities, and polysomnography results of the two groups were compared. The independent risk factors associated with hypertension in patients with OSA were explored. Results A total of 1108 patients with OSA initially diagnosed were included in the study, including 387 with hypertension and 721 without. Compared with OSA patients without hypertension, OSA patients with hypertension were older; had a higher body mass index (BMI) and Epworth sleepiness score (ESS); a higher incidence of nocturia; and a higher proportion of diabetes mellitus, coronary heart disease, and cerebrovascular disease. Multivariate analysis showed age (odds ratio [OR]:1.06, 95% confidence interval [CI]:1.04-1.08), BMI (OR:1.17, 95% CI:1.11-1.23), ESS score (OR:0.97, 95%CI: 0.94-1.00) and nocturia symptoms (OR:1.64, 95% CI:1.19-2.27) was independently associated with hypertension in OSA patients, and comorbid diabetes (OR: 3.86, 95% CI: 2.31-6.45), coronary heart disease (OR: 1.90, 95% CI:1.15-3.16), and ischemic stroke (OR: 3.69,95% CI:1.31-10.40) was independently associated with hypertension in OSA patients. Conclusion Compared to OSA patients with normal blood pressure, OSA patients with hypertension had more significant daytime sleepiness, more frequent nocturnal urination, and a higher risk of diabetes, coronary heart disease, and cerebrovascular disease.


Introduction
Obstructive sleep apnea (OSA) is the most common sleeprelated breathing disorder and is characterized by recurrent complete or partial collapse of the upper airway at night, leading sleep fragmentation and frequent nocturnal hypoxia.Approximately 936 million adults aged 30-69 suffer from OSA worldwide; China has the largest number of OSA patients in the world, with a prevalence of 23.6% in people aged 30-69 (1).As the population ages and the prevalence of obesity increases, the prevalence of OSA is also likely to increase rapidly.OSA can cause a series of pathophysiological results such as chronic intermittent hypoxia, oxidative stress and inflammatory response, increased negative pressure in the pleural cavity, and increased sympathetic nerve activity (2).Patients with OSA may present with a variety of symptoms, including habitual snoring, fatigue, poor sleep quality, excessive daytime sleepiness (EDS), memory loss, headaches, and psychological disturbances (3).Many studies have confirmed that untreated OSA can damage multiple systems and organs and cause a variety of complications, including cardiovascular diseases, ischemic stroke, metabolic-related diseases, and neuropsychiatric complications (4)(5)(6)(7).
OSA and hypertension are closely associated.The prevalence of OSA in hypertensive patients is approximately 50%, the prevalence of OSA in patients with resistant hypertension is up to 71%, and the incidence of hypertensive crisis in OSA patients with hypertension is 15.70% (8).Approximately 30 to 50% of patients with OSA also have hypertension, which increases the risk of cardiovascular disease and cardiovascular death in these patients (9).Kario et al. found that OSA-related hypertension has the following features, which is usually characterized by increased diastolic blood pressure and nocturnal hypertension typically presents with nocturnal blood pressure may be non-descending (a small or absent nocturnal blood pressure drop) or ascending (nocturnal blood pressure higher than daytime blood pressure) (10).Cai et al. found that the incidence of occult hypertension in patients with OSA was higher than that in those without OSA, and the incidence of occult hypertension in subjects newly diagnosed with OSA was close to 30% (11).OSA induces intermittent hypoxia, which causes oxidative stress and inflammation, leading to vascular endothelial dysfunction, reduces the availability of nitric oxide and vascular endothelial relaxation ability, upregulates sympathetic nerve excitation, and causes vasoconstriction, increased vascular resistance, and vascular remodeling.Hypoxia leads to the activation of the reninangiotensin-aldosterone system (RAAS), which in turn leads to hypertension (12-16).
To date, the clinical characteristics of patients with OSA and hypertension have not been fully clarified, and only individual studies have been conducted in Western countries.Moreover, OSA is a heterogeneous disease with some racial differences.Craniofacial structure differences have been proposed as one of the important reasons for the greater susceptibility of Asians to OSA (17).Besides, ethnic differences in body fat distribution, the impact of BMI on AHI and genetic susceptibility may be other factors of OSA characteristics in Asian populations (18,19).This study examined the association of coexisting hypertension with OSA-related symptoms, other comorbidities, and polysomnography (PSG) outcomes in Chinese patients with OSA at first diagnosis.

Study participants
This retrospective study used data from January 2016 to December 2020; 1257 patients who were admitted to the affiliated Lihuili Hospital of Ningbo University with suspected sleep disordered breathing underwent full-night PSG examination, and adult patients with newly diagnosed OSA were included in this study.The exclusion criteria were age<18 y, simple snoring, central sleep apnea, mixed sleep apnea, previous PSG and/or continuous positive airway pressure treatment, and incomplete clinical data.A total of 1108 patients met the inclusion criteria, including 387 with hypertension and 721 without hypertension.Hypertension in this study was defined according to Chinese Guidelines for the Prevention and Treatment of Hypertension: In the absence of antihypertensive drugs, room blood pressure was measured three times on different days, SBP≥140mmHg and/or DBP≥90 mmHg or the patient's history of a definite diagnosis of hypertension.The grouping flow chart is presented in Figure 1.The study was approved by the Ethics Committee of The Affiliated Lihuili Hospital of Ningbo University (Approval Number: KY2021PJ241) and written informed consent was obtained from each participant.

Data collection
Age and sex of the participants were obtained from an inpatient system.Professional nurses measured the height, weight, and awake pulse oxygen saturation of the participants.Detailed medical histories of the participants, including comorbidities and other diseases, were collected and recorded by professional respiratory physicians.Daytime sleepiness was assessed using the Epworth Sleepiness Scale (ESS).Body mass index (BMI) was defined as kg/m 2 .

Polysomnography
Participants underwent full-night PSG monitoring in the hospital's sleep-monitoring room and were asked to avoid alcohol, tea, coffee, sedation, and hypnotic drugs that day.We had used a polysomnographic system (Alice 5, Respironics, Philips, Pittsburgh, Pennsylvania, USA) to test at least 7 hours of sleep.The monitoring items included electroencephalography, electrocardiography, electroophthalmography, mandibular electromyography, oronasal airflow, snoring, chest and abdominal movements, body position, and pulse oxygen saturation.

Data analysis
Continuous variables which conform to normal distribution are expressed by mean and standard deviation, those that do not conform to normal distribution are expressed by median (quartile), and categorical variable data are expressed by percentage.The t-test or analysis of variance (ANOVA) were used to compare continuous variables, and the chi-squared test was used to compare categorical variables.Multivariate analysis was performed using binary logistic regression.SPSS26.0 statistical analysis software was used for statistical analysis, and a P value <0.05 was considered statistically significant.

Sociodemographic characteristics
The sociodemographic characteristics of the 1108 patients with OSA are shown in Table 1.There were 387 patients with hypertension and 721 patients without hypertension, respectively.The average age of the total patients was 45.30 ± 11.58 y; the average age of patients with and without hypertension was 50.31 ± 10.92 and 42.6 ± 11.03 y, respectively.The mean age of patients with hypertension was significantly higher than that of patients without hypertension (P < 0.001).There was a significant increase in BMI (P < 0.001) and ESS scores (P =0.048) in patients with hypertension.The proportions of obese patients (P < 0.001) and smokers (P =0.003) with hypertension were significantly higher.No differences in sex or alcohol use were observed between OSA patients with and without hypertension.

Clinical symptoms
Table 2 shows the clinical symptoms of total patients with OSA and those with or without hypertension.The proportions of patients waking up at night (P =0.015), mouth dryness (P=0.010),nocturia (P =0.010), memory deterioration(P<0.010), and impatient personality (P=0.010) were significantly increased in OSA patients with hypertension.There were no differences in the ratio of morning headache, daytime sleepiness, impact on quality of life, work, or traffic safety.Flow chart of the patients' inclusion process.PSG, polysomnography; OSA, obstructive sleep apnea; PAP, positive airway pressure.

Clinical comorbidities
Other clinical comorbidities are shown in Table 3.The proportions for diabetes mellitus (P <0.010), coronary heart disease (P <0.010), chronic obstructive pulmonary disease (P =0.045), and ischemic stroke (P <0.010) were significantly higher in OSA patients with hypertension.There were no statistically significant differences in the proportions of gastroesophageal reflux and thyroid disease between OSA with and without hypertension.

Multi-variate analysis
When controlling for sociodemographic features, clinical symptoms, comorbidities, and PSG results (Table 5), binary logistic regression analysis suggested that age, BMI, ESS score, nocturia, diabetes, cardiovascular disease, and ischemic stroke were independently associated with hypertension in OSA patients.

Discussion
OSA is a complex and heterogeneous disease with multiple pathophysiological results such as chronic intermittent hypoxia, oxidative stress, inflammatory response, increased negative pressure in the chest, and increased sympathetic activity (2).Peppard et al. found a dose-effect relationship between baseline sleep-disordered breathing and hypertension after four years, independent of known confounding factors (20).This suggests that the risk of developing hypertension increases with AHI.Sleep in patients with OSA is highly fragmented, with a higher proportion of light sleep; the proportion of slow wave sleep (SWS) is significantly decreased, and SWS stage is accompanied by lower sympathetic nervous activity and higher parasympathetic nerve activity (3,21).Experimental inhibition of human SWS can significantly reduce the drop in blood  (30).
The most commonly used quantitative method to assess the degree of daytime sleepiness is the subjective ESS.When the ESS score was greater than 10 was defined as EDS (31).EDS has become one of the most common and prominent symptoms in patients with OSA and is an important criterion for its diagnosis and treatment (32,33).In this study, we found that the ESS score of OSA patients with hypertension was significantly higher than that of those without hypertension.Kapur et al. suggested that participants with sleep-disordered breathing who often felt excessively sleepy were more likely to develop high blood pressure than those who did not (34).Feng et al. found that OSA patients with higher ESS scores were more likely to have higher blood pressure than OSA patients with lower ESS scores, and even had a higher risk of being diagnosed with hypertension (35).Robinson et al. reported that EDS hypertensive patients with OSA experienced a decrease in blood pressure after receiving continuous positive airway pressure (CPAP) compared without EDS hypertensive patients (36).This suggests that daytime sleepiness may be related in some way to the pathogenesis of hypertension in sleep apnea.However, contrary results have also been reported in the literature.Martynowicz et al. found that in the moderate to severe OSA group, the total ESS score of hypertensive patients was significantly lower than that of patients with normal blood pressure (37).This may be because the ESS relies on patient self-reporting, and is susceptible to subjective factors.
Nocturia refers to the occurrence of two or more urinations at night (38).The main causes of nocturia include inflammation, benign prostatic hyperplasia, excessive bladder activity, neurogenic bladder, and OSA.Nocturia and nighttime hypertension are common in patients with obstructive sleep apnea (OSA) and share several physiopathological pathways (27).AHI is an independent predictor of nocturnal urination frequency in OSA patients (39).Nocturia became more common as the severity of OSA increased.OSA may lead to nocturia by several mechanisms: OSA can lead to airflow obstruction, intermittent hypoxia, sympathetic hyperactivity, and changes in thoracic pressure, resulting in atrial and ventricular secretion of atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP), stimulating water and sodium excretion, inhibiting RAAS and antidiuretic  (44).Although the pathophysiological mechanism of the association between hypertension and nocturia has not been fully established, several hypotheses have been proposed.First, higher daytime blood pressure may reflect higher nighttime blood pressure, which promotes natriuresis (45).Hypertension can lead to nocturia through changes in glomerular filtration rate and tubular transport (46).Nocturnal polyuria due to RAAS activation, a corresponding increase in nocturnal sodium in the urine, and decreased bladder function due to chronic vascular insufficiency are mediated by hypertension and other atherosclerotic risk factors (47).Congestive heart failure due to hypertension leads to atrial extension, increased release of atrial natriuretic peptide (ANP) and increased nocturia due to renal hyperfiltration (48).Therefore, nocturia was more frequent in OSA patients with hypertension than in those without hypertension.
Diabetes is a common comorbidity of OSA, and increasing evidence supports a complex relationship between OSA and diabetes.Intermittent hypoxemia and sleep disruption can lead to activation of the sympathetic nervous system, increased oxidative stress, dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis, and systemic inflammation.Sympathetic activation leads to increased levels of catecholamines such as norepinephrine and epinephrine, inducing insulin resistance, inhibiting pancreatic insulin secretion, and resulting in elevated blood sugar (49).Adrenaline can also promote hepatic glucose production and inhibit insulin secretion, and the uptake of glucose by tissues further increases blood glucose uptake (50).OSA can lead to a significant reduction or inhibition of SWS (21), and Herzog et al. found that selective suppression of SWS resulted in an increase in plasma glucose and a decrease in insulin sensitivity in the early morning (51).However, several studies have found that the relationship between OSA and type 2 diabetes may be bidirectional, and that diabetic neuropathy can affect central respiratory control and the upper respiratory tract nerve reflex and promote sleepdisordered breathing (52).Diabetes and hypertension have overlapping genetic, physiological, and environmental factors, and ).The strong association between OSA and coronary and cerebrovascular disease appears to be independent of shared risk factors, including obesity (60).Most studies have shown a causal relationship between OSA severity (as assessed using AHI) and the risk of cardiovascular events (61).It has also been found that the risk of stroke in patients with mild OSA is 2.44 times higher than that in normal people, while the risk of stroke in patients with moderate or severe OSA is 3.56 times higher than that in normal people (62).This indicates that the severer OSA is, the more likely it is to be complicated with cardiovascular and cerebrovascular diseases.Previous studies have found that the relationship between OSA and cardiovascular disease risk factors is bidirectional, suggesting that patients with cardiovascular disease may also develop OSA and that effective treatment of cardiovascular disease may improve OSA (63).Compared with patients without hypertension, hypertension also significantly increases the risk and severity of cardiovascular and cerebrovascular diseases (64).High blood pressure is an intermediary between OSA and cardiovascular disease, and its presence of high blood pressure also increases the risk of cardiovascular development in patients with OSA, ultimately increasing the risk of cardiovascular-related death (65).In addition, OSA has been shown to be an independent risk factor for hypertension, ischemic heart disease, and arrhythmia, which in turn constitute risk factors for ischemic stroke (66).Therefore, hypertensive OSA is associated with a significantly increased risk for cardiovascular and cerebrovascular diseases.
The advantage of this study is that the sample size was large, covering all genders and age stages, and the sample data were rich, including sociodemographic features, clinical characteristics, and PSG results.However, this study also had some limitations.First, ambulatory blood pressure monitoring was not performed in this study and data of blood pressure at night were unavailable.Second, there was no subgroup analysis of hypertension level.

Conclusion
In conclusion, our study found that patients with OSA and hypertension had more severe daytime sleepiness and more frequent nocturnal urination than OSA patients without hypertension.Simultaneously, there is a higher risk of combining with diabetes, coronary heart disease, and ischemic stroke.This indicates that the patients with OSA combined with hypertension had more symptoms and a heavier burden of cardiovascular, and cerebrovascular, and metabolic complications.More attention should be paid to these patients, and individualized treatment should be provided in clinical practice.The author(s) declare that financial support was received for the research, authorship, and/or publication of this article.

FIGURE 1
FIGURE 1 This work was funded by the Science and Technology Program for Public Welfare of Ningbo, China (grant number 2021S175) and the Medical Science and Technology Program of Ningbo, China (grant number 2020Y03).

TABLE 1
Sociodemographic characteristics of total OSA patients and the patients with or without hypertension.

TABLE 2
Clinical features of total OSA patients and the patients with or without hypertension.

TABLE 3
Clinical comorbidities of total OSA patients and the patients with or without hypertension.

TABLE 4
PSG result of total OSA patients and the patients with or without hypertension.

TABLE 5
Independent risk factors of OSA patients with hypertension.T90, percentage of recording time with SaO 2 <90 hypertension may be considered as an important cause of diabetes (53, 54).Diabetic complications are more common in patients with OSA and hypertension than in those without.Luo et al. found that non-falling blood pressure in hypertensive patients with OSA was associated with an approximately 1.5-fold increased risk of new-onset diabetes (55).This suggests that hypertension in OSA may induce or B-value, log-odds; OR, odds ratio; BMI, body mass index; ESS, Epworth Sleepiness Scale; AHI, apnea-hypopnea Index; ODI, oxygen desaturation index;