Levels of type B natriuretic peptide in patients with obstructive sleep apnea

PhD, Associate professor of department of internal medicine, family medicine, occupational medicine and medical rehabilitation, State Institution “Zaporizhzhia Medical Academy of Post-Graduate Education Ministry of Health of Ukraine”, Zaporizhzhia, Ukraine

Results

The aim of this study was to analyze the possible association between OSA and levels of BNP in a community-based sample of patients.

Matherials and methods. This was a prospective, controlled, cross-sectional study performed between 2013 and 2014. We included subjects older than 18 years with suspected OSA and without cardiovascular pathologies. During the study, 82 subjects met the inclusion/exclusion criteria and were enrolled in this study: 57 patients with OSA and 25 healthy normotensive subjects as controls. Each patient underwent a clinical evaluation during the consultation (with measurement of body mass and height), surveys with questionnaires, biological tests, cardiorespiratory monitoring.

The serum NTproBNP levels were significantly higher (p-0,0001) in the OSA group (22,39±4,79 pg/ml) than in the control group (9,29±6,75 pg/ml). Increased serum NTproBNP levels were significantly associated with mean transcutaneous oxygen saturation (SpO2) (p=0,0001), minimal SpO2 (p=0,002), oxygen desaturation index (p=0,001), and total sleep time spent with SpO2 lower than 90% (p=0,002). All patients with elevated NTproBNP levels (67 pg/ml) had moderate or severe OSA. The more severe the OSA, the higher the NTproBNP levels were. However, only the difference between severe and mild OSA was statistically significant (p=0,029).

Conclusions. Level of NTproBNP significantly increased in patients with OSA in comparison with healthy subjects. NTproBNP might then be suggested as a potential marker for screening of preclinical cardiovascular damage in patients with untreated OSA. Therefore, more research is needed before making any definitive conclusions.

Key words: natriiuretic peptide, obstructive sleep apnea, biomarkers

Obstructive sleep apnea-hypopnea syndrome (OSA) is a common sleep-related breathing disorder that occurs in about 4-7% of the general adult population [1]. It is characterized by recurrent episodes of complete or partial upper airway obstruction during sleep, resulting in oxygen desaturation, sleep fragmentation, and daytime sleepiness [2].

Recent studies have shown a large body of epidemiologic evidence linking the OSA with important cardiovascular morbidity and mortality [3]. However, the underlying pathophysiologic mechanisms are not fully understood, nor is the potential role of cardiac biomarkers in these states. Recently, there has been growing interest in the potential relationship between OSA and brain natriuretic peptide (BNP) regulation [4].

There are 3 major NPs, atrial natriuretic peptide (ANP), B-type natriuretic peptide (BNP), and C-type NP, all of which share a common 17-amino-acid ring structure and have actions that are targeted at protecting the cardiovascular system from the effects of volume overload [5]. The ANP and BNP are released primarily from the heart but circulate as hormones to act in various tissues in the body and induce vasodilation, natriu- resis, and diuresis [6]. Although ANP is preferentially synthesized and secreted from the atria and BNP from the ventricles, both can be synthesized in either chamber under pathologic conditions. Unlike ANP, which is stored in granules and thus released with even minor triggers such as exercise, BNP has minimal storage in granules; rather, it is synthesized and secreted in bursts. C-type NP, derived primarily from endothelial cells, is also synthesized in myocardial tissue and might protect against remodeling effects in the post-myocardial infarction setting [7].

In the setting of volume expansion or pressure overload, the resulting wall stress initiates synthesis of pre-proBNP in the ventricular myocardium. Subsequently, the peptide is cleaved first to proBNP [8], then to the biologically active BNP [6] and the inactive amino-terminal fragment (NTproBNP). The release of BNP results in improved myocardial relaxation and serves an important regulatory role in response to acute increases in ventricular volume by opposing the vasoconstriction, sodium retention, and antidiuretic effects of the activated renin-angiotensin-aldosterone system [9]. The biological actions of NPs are mediated through membrane-bound natriuretic peptide receptors (NPRs) that are linked to a cyclic guanosine monophosphate-dependent signaling cascade, including NPR-A, which preferentially binds ANP and BNP, and NPR-B, which preferentially binds C-type NP. Clearance of NPs from the blood is mediated by NPR-C. In addition, BNP is degraded by neutral endopeptidase, which opens the ring structure and inactivates the peptide [10].

Because OSA has been suggested as a probable cause of increased ventricular load and therefore ventricular distension during periods of apnea, it has been proposed that BNP levels could be useful as a diagnostic and prognostic marker in patients with OSA [6].

Recently, an ideal biomarker for sleep apnea was described, citing that the optimal biomarkers would have use as a diagnostic measure, a means for assessing disease burden and severity, and a method for measuring response to treatment. For diagnostic utility, an ideal biomarker would need to be both sensitive and specific, which in theory, could obviate the need for polysomnography, at least in some patients [11].

Previous studies on the association between biomarkers and the presence and severity of OSAHS have revealed conflicting results [7]. While some studies reported increasing levels of BNP in patients with OSAHS [8] and reduced BNP levels with continuous positive airway pressure (CPAP) treatment [9], others have not found any association [10]. In addition, most studies are small and based on symptomatic patients referred to sleep clinics. Therefore, the association between OSA and BNP levels in the general population remains largely unknown [10].

The aim of this study was to analyze the possible association between OSA and levels of BNP in a community-based sample of patients.

Matherials and methods. This was a prospective, controlled, cross-sectional study performed between 2013 and 2014. The study was approved by the local ethics committee, and informed consent was obtained from each patient enrolled in the study.

We included subjects older than 18 years with suspected OSA and without cardiovascular pathologies.

Exclusion criteria included refusal to participate in the study, previously diagnosed sleep-disordered breathing, chronic obstructive pulmonary diseases or other severe lung disorders, a history of cerebrovascular or cardiovascular events, uncontrolled hypertension, psychiatric disorders, diabetes mellitus, hyperlipidemia, hypercholesterolemia, malignancy, inflammatory diseases, dysthyroidism, a history of recent facial trauma/operation, pregnancy, and the use of sedatives or muscle relaxants.

During the study, 82 subjects met the inclusion/exclusion criteria and were enrolled in this study: 57 patients with OSA and 25 healthy normotensive subjects as controls.

Patient history was obtained with the help of a structured interview. We collected demographic variables (age, sex), current cigarette smoking status, history of preexisting diseases, and current drug use. Daytime sleepiness was estimated using the Ukrainan version of the Epworth sleepiness scale (ESS). In addition to standard physical examination, neck circumference, body weight, and height were measured. Body mass index (BMI) was calculated as kg/m². Daytime blood pressure was measured in the right upper arm using an automatic oscillometric device after a rest of at least 10 min in a seated position. The main awake blood pressure was calculated based on three measurements on the day of admission. Patients were considered normotensive if they had no history of hypertension, their systolic blood pressure was <139 mmHg, and their diastolic blood pressure was <89 mmHg.

Cardio-respiratory monitoring was performed using cardiorespiratory monitor Somnocheck Effort (Weinmann, Germany). All participants were recorded for at least 8 hours. An apnoea was defined as a complete cessation of airflow for >10 s, and a hypopnoea as a >50% reduction in the nasal pressure signal or a 3050% decrease, associated with either oxygen desaturation of >3% or an arousal (defined according to the Chicago report or by autonomic activations on pulse transit time), both lasting for >10 s. The apnea-hypopnea index (AHI) was defined as the number of apneas and hy- popneas per hour of sleep. According to the American Association of Sleep medicine [5], the severity of OSAS was classified as mild (5<AHI<15 events/hour), moderate (15 <AHI<30events/hour) and severe (AHI>30 events/hour). Desaturation index (DI) was defined as the percentage of sleep time with oxygen satu- ration<90%. Also we estimated mean and minimal SaO2. All subjects didn't have previous treatment of OSAS.

Laboratory evaluation included measurement of NT-proBNP along with other routine investigations as per clinical judgment. For NT-proBNP measurement, blood samples were drawn in nonfasting state. Determination of serum NT-proBNP was done by electrochemiluminescence immunoassay (Vector-best, Russia federation).

Statistical analysis was performed using SPSS 23 (SPSS, Inc., Chicago, IL, USA) for Windows. Data are presented as frequencies, percentages, mean±standard deviation, or median. Differences between consecutive NT-proBNP values were assessed by a one-way analysis of variance test with a Bonferroni correction. A value of p<0.05 was considered significant.

The OSA and control groups were similar in age, sex distribution, BMI, smoking status, and blood pressure. In addition, patient demographics (age, sex, and smoking status) were similar in the three study groups. However, BMI was significantly higher in OSA patients in comparison with control group (p=0,032). Based on the ESS, patients with OSA were significantly more somnolent than control subjects (^=0,013). Similarly, the mean ESS was significantly higher in OSA patients than control patients (^=0,015). The oxygen desaturation index (ODI) was significantly higher in OSA patients in comparison with controls (p=0,0001). Spirometric measurements (FEV1, FVC, and FEV1/FVC) did not differ among the four groups. The baseline characteristics of the final study population are shown in the Table 1.

Table 1 Clinical characteristics, results of sleep studies, and spirometric measurements: comparison of OSA patients and controls

Subjects were also divided into two groups based on whether the NTproBNP level was above or below the cut-off value. At first presentation, the plasma levels of NTproBNP in all subjects ranged from 1,9 to 97 pg/ml, with a median of 36,99 ± 4,17 pg/ml.

Patients with increased levels of BNP were significantly older than those with normal levels (p=0,003). In contrast, low or high levels of NTproBNP were not associated with sex ratio, BMI, smoking status, ESS, blood sugar blood levels, or creatinine clearance. Increased levels of NTproBNP were significantly more frequent among patients with OSA (25,6%) in comparison with the control group (0%) (p=0,011). Similarly, the serum NTproBNP levels were significantly higher in the OSA group (22,39±4,79 pg/ml) than in the controls (10,33±4,65 pg/ml) (p=0,0001). In addition, increased serum NTproBNP levels were significantly associated with mean transcutaneous oxygen saturation (SpO2) (p<0,0001), minimal SpO2 (p=0,002), ODI (p=0,001), and total sleep time with SpO2<90% (p=0,002).

NTproBNP levels by OSA classification are shown in Table 2. All patients with high NTproBNP levels had moderate or severe OSA. There was also a dose response relationship between increasing severity of sleep apnea and elevated NTproBNP. However, only the difference between severe and mild OSA was statistically significant (p=0,029).

cardiovascular sleep apnea natriuretic

Table 2. Level of NT-proBNP according severity of OSA

In comparison with group with different level of NTproBNP elevation, there were no significant differences between the two groups in age, sex ratio, smoking status, BMI, average blood pressure, ESS, spiro- metric indices, or creatinine clearance. In participants with high AHI, mean SpO2 and minimal SpO2 were significantly lower (p<0,001), while blood sugar levels were significantly higher (p=0,029), as well as mean NTproBNP level (22,39±14,79 pg/ml vs. 9,29±6,75 pg/ml, p<0,0001). This association between high baseline AHI and higher baseline NTproBNP levels remained after adjustment for confounders of blood sugar levels.

In the univariate regression model, there was a linear association between variables of sleep apnea and plasma NTproBNP. For AHI and ODI, this association remained after adjustment for the confounders of age and BMI, as well as after adjustment for systolic blood pressure. Results from the Spearman rank correlation test and Spearman partial rank correlation showed no difference compared with the results from the multiple linear regression models.

In this study, we showed that the serum NTproBNP level was significantly increased in patients with OSA in comparison with controls. The two groups were closely matched for almost all confounding variables such as age, BMI, blood pressure, and renal function. The higher blood sugar level in the OSA group was the only difference. After adjustment, a significant correlation between NTproBNP level and OSA was identified. We also show that the elevated level of BNP is positively correlated with the severity of OSAHS, independent of obesity. Our results indicate that NTproBNP is sensitive enough to detect myocardial stress caused by OSA and could be used as a sensitive marker for underlying preclinical cardiovascular changes in patients with OSA [6]. Our finding is in accordance with some previous studies. In a community based sample of 349 women, Ljunggren et al. [8] found a relationship between the severity of sleep apnea during the night and the levels of plasma BNP in the morning that cannot be explained by known confounding factors. The same conclusion was reached by Kaditis et al. [12]

Many hypotheses have been suggested to explain how OSA might contribute as a stimulus of natriiuretic release. It is well known that BNP is primarily secreted by the left ventricular myocytes in response to cardiac wall stretching. Hypoxia has also been reported to in duce BNP secretion. In contrast, we know that exaggerated negative intrathoracic pressure and its repetitive fluctuations during nightly apnea episodes markedly increases ventricular transmural pressure and left ventricular afterload, as well as the end-systolic and end-diastolic volume during sleep. Indeed, all of them together may give rise to both pressure load and volume expansion. Furthermore, sustained activation of the sympathetic nervous system and intermittent nocturnal hypoxemia may also contribute. Repetitive rise in blood pressure may also add by inducing myocyte damage and increasing blood BNP levels. Based on these findings, some authors, such as Maeder et al. [13], have claimed that the high level of BNP is a convenient marker for detecting cardiovascular damage. Nevertheless, there is still uncertainty about whether OSA affects BNP, as several other studies have reported different data. In a prospective study on 60 consecutive patients, Hubner et al. [6] did not find any correlation between N-terminal pro-brain natriuretic peptide (NT- pro-BNP) and AHI or other sleep-related indices. In multiple regression analysis, NT-pro-BNP was significantly correlated with left ventricular ejection fraction, creatinine, clearance, and the presence of arterial hypertension but not with AHI. Likewise, Cifc.i et al. [14] evaluated 33 patients with OSA and did not find statistically significant increases in the levels of serum BNP. Consequently, they concluded that OSA does not induce enough myocardial damage to increase serum BNP levels. Tasci et al. [9] found that OSA did not affect BNP levels even in hypertensive OSA patients, in contrast to our study. Recently, Maeder et al. [7] showed that significant OSA is associated with a more pronounced overnight reduction in BNP. However, they could not find any significant differences in NTpro-BNP between patients with moderate or severe OSA and those with mild or no OSAHS.

NTproBNP is produced and secreted from the myocytes in response to cardiac wall stretch. Hypoxia has also been reported to induce NTproBNP secretion. In our study, there was a strong association between AHI and morning levels of plasma NTproBNP, which might be explained by a change in intrathoracic pressure during the nightly apnea episodes. The negative intratho- racic pressure during each apnea episode increases ventricular transmural pressure and left ventricular afterload, as well as the end-systolic and end-diastolic volume, giving rise to both pressure load and volume expansion. Increased sympathetic nervous activity caused by repetitive apnea episodes with arousal and hypoxia, which leads to peripheral vasoconstriction and tachycardia, may also contribute. The increased left ventricular transmural pressure increases myocardial oxygen demand and reduces coronary blood flow and, in combination with the apnea-related hypoxia, may lead to myocardial ischemia and impaired cardiac contractility. Even in asymptomatic individuals without known cardiovascular disease, elevated levels of NTproBNP are associated with an increased risk of cardiovascular events, heart failure, and death. OSAS is an independent risk factor for hypertension and is associated with an increased risk of ischemic heart disease, stroke, and heart failure. The cutoff value of NTproBNP in our study is lower than the thresholds used clinically to diagnose heart failure.

Conclusions. Level of NTproBNP significantly increased in patients with OSA in comparison with healthy subjects. NTproBNP might then be suggested as a potential marker for screening of preclinical cardiovascular damage in patients with untreated OSA. Therefore, more research is needed before making any definitive conclusions.

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