Nocturia in Patients With Sleep-Disordered Breathing and Cardiovascular Disease

Takashi Miyazaki; Sunao Kojima; Megumi Yamamuro; Kenji Sakamoto; Yasuhiro Izumiya; Kenichi Tsujita; Eiichiro Yamamoto; Tomoko Tanaka; Koichi Kaikita; Seiji Hokimoto; Hisao Ogawa

doi:10.1253/circj.CJ-15-0654

Abstract

Background: Sleep apnea is a common condition and a cardiovascular risk factor. Continuous positive airway pressure (CPAP) reduces cardiovascular events and sleep apnea-related symptoms, especially in patients with obstructive sleep apnea (OSA), who occasionally experience nocturia, a common problem in individuals of advanced age.

Methods and Results: The present study was a prospective, observational study including 1,429 consecutive patients with cardiovascular disease (CVD). A questionnaire on nocturia was administered and nocturnal pulse oximetry was performed. Patients with moderate-to-severe sleep-disordered breathing (SDB) underwent polysomnography, and patients with OSA received CPAP therapy. Nocturia was observed in 561 of 666 patients included in the analysis. A multiple logistic regression analysis revealed that nocturia was associated with oxygen desaturation defined as a 3% decrease (P=0.0335) independent of age (P<0.0001), male sex (P=0.0078), hypertension (P=0.0139), and B-type natriuretic peptide (BNP) level (P=0.0185). Nocturia was reduced in patients who continued CPAP treatment and they also showed a decrease in the apnea-hypopnea index (45.3±13.6 vs. 2.5±3.7 events/h, P<0.0001), systolic blood pressure (121.6±11.9 vs. 113.4±8.8 mmHg, P=0.0002), and BNP level (57.7 [15.0–144.4] vs. 27.4 [8.5–111.7] pg/ml, P=0.0006).

Conclusions: CPAP has the potential to reduce nocturia and risk factors for SDB such as increased blood pressure and BNP level, which may be beneficial in older men with CVD and OSA.

Sleep apnea syndrome and its treatment have recently received increased attention.¹^,² Sleep-disordered breathing (SDB), most frequently manifesting as obstructive sleep apnea (OSA), is a common syndrome and becomes progressively more prevalent with increasing age.³ Obstructive SDB covers a spectrum of airway collapse, ranging from primary snoring to profound OSA. Repeated cycles of hypoxemia and reoxygenation are thought to play a critical role in augmenting sympathetic activation, cardiovascular variability, vasoactive substance levels, inflammation, oxidative stress, endothelial dysfunction, thrombosis, and intrathoracic pressure changes.⁴ OSA is associated with an increased risk of cardiovascular disease (CVD).⁵^–⁷ Recent data have demonstrated a strong association between untreated OSA and cardiovascular morbidity and mortality.⁸^,⁹ Treatment of OSA improves hypoxia caused by transient interruption of breathing and stabilizes cardiovascular function.⁴ Continuous positive airway pressure (CPAP) is a first-line treatment and may reduce the incidence of cardiovascular events in patients showing optimal adherence.¹⁰

The major signs and symptoms associated with OSA are excessive daytime sleepiness, loud snoring, and a number of arousals.¹¹ Patients with OSA occasionally experience nocturia, which is a particularly important issue in patients of advanced age, as it may impair their quality of life.¹² The major complaint in patients with nocturia is waking up at night one or more times to void.¹³ Furthermore, nocturia in elderly people is associated with high mortality rates.¹⁴ Therefore, nocturia associated with OSA is a serious problem in aging populations, although the prevalence of OSA has been frequently underestimated in patients with CVD.

The Portable Monitoring Task Force of the American Academy of Sleep Medicine recommends that portable monitoring restricted to type 3 devices (usually using 4–7 channels) should be limited to patients with moderate-to-severe OSA.¹⁵ Fully-equipped sleep studies are not feasible for all hospitalized patients; therefore, pulse oximetry, which is a typical type 4 device (1 or 2 channels, usually using oximetry as one of the parameters),¹⁵^,¹⁶ is considered an alternative. Nocturnal pulse oximetry is a comprehensive screening method for the diagnosis of OSA.¹⁷ Simple monitoring with pulse oximetry may be clinically useful in providing essential information on the severity of SDB. Early detection and intervention with a screening tool in patients with SDB may not only reduce sleep apnea-related symptoms but also improve quality of life and prevent future cardiovascular events in this patient group.

Our study used nocturnal pulse oximetry with the aim of assessing whether nocturia was associated with SDB and to determine whether CPAP had a clinically beneficial effect on nocturia in patients with CVD and OSA.

Methods

Patient Enrollment

The present study was an observational, prospective study of 1,429 consecutive patients with CVD referred to Kumamoto University Hospital for medical investigation and treatment between February 2013 and July 2014. Patients requiring emergency hospital admission, those who had worsening clinical status despite elective admission, and those who refused to participate in the study were excluded. Patients undergoing hemodialysis, those with invalid oximetry values, those who removed their own pulse oximeter during sleep, and those with insufficient data on nocturia were also excluded.

Risk factors for CVD were defined as hypertension (>140/90 mmHg or use of antihypertensive medications), diabetes mellitus (fasting plasma glucose level ≥126 mg/dl, 2-h value ≥200 mg/dl in the 75-g oral glucose tolerance test, casual plasma glucose level ≥200 mg/dl, hemoglobin A_1c ≥6.5%, or use of medications for diabetes mellitus),¹⁸ dyslipidemia (high-density lipoprotein cholesterol <40 mg/dl, low-density lipoprotein cholesterol ≥140 mg/dl, or use of lipid-lowering medications), and current smoking (smoking within 1 year preceding the study). The estimated glomerular filtration rate was calculated from the Japanese equation: glomerular filtration rate (ml/min/1.73 m²)=194×serum creatinine^−1.094 ×age^−0.287 (if female, ×0.739).¹⁹

Study Protocol

A standard commercially available cardiac ultrasound machine (Vivid 7, General Electric Medical Systems, Milwaukee, WI, USA) was used to perform resting echocardiography in the enrolled patients. Pulsed-wave Doppler recordings of left ventricular (LV) inflow were acquired from the apical 4-chamber view with the sample volume placed between the tips of the mitral leaflets, and peak early (E) and late diastolic flow velocities were assessed. Pulsed-wave tissue Doppler was performed to establish peak early diastolic mitral annular velocity (e’). The ratio of mitral inflow early diastolic velocity to the average e’ velocity obtained from the septal and lateral sides of the mitral annulus (E/e’) was calculated to estimate LV filling pressure.²⁰

Nocturia is a complaint in which an individual has to wake at night one or more times to void, which each voiding being preceded and followed by sleep.¹³ In this study, nocturia was defined as nighttime waking and going to urinate after sleep. Nocturnal urination before going to sleep or the first morning urination was not regarded as nocturia. Patients were asked about the frequency of nocturia over the past 4 weeks on hospital admission by a medical clerk who was blinded to the patients’ background, and the data were included in the validated Nocturia, Nocturnal Enuresis, and Sleep-interruption Questionnaire (NNES-Q), which was modified for this study.²¹ Nocturnal pulse oximetry was performed in all patients on day 1 of hospitalization over one night using a pulse oximeter (Pulsox^®-Me300; Konica Minolta, Osaka, Japan) placed on the subject’s index finger with a flexible probe. The pulse oximeter was attached at 9:00 pm and removed at 6:00 am the next morning by trained nurses. After removal of the pulse oximeter, vital signs were checked and fasting blood samples were also collected. The oxygen desaturation index (ODI), which denotes the number of desaturations per hour, cumulative time with arterial oxyhemoglobin saturation by pulse oximetry (SpO₂) <90%, lowest and average SpO₂, and average pulse rate were extracted from the oximetry data and scored using specific software (DS^®-Me; Konica Minolta) by a technician who was blinded to the patients’ background. In the present study, oxygen desaturation was defined as a decrease of 3% or higher in the saturation level per hour (3%ODI). Additionally, the 3%ODI was used to indicate the likely presence of SDB: 5 to <15 events/h was considered as mild SDB, 15 to <30 events/h was considered as moderate SDB, and >30 events/h was considered as severe SDB.²²

For a diagnosis of OSA, full-night polysomnography (EEG-9200 Neurofax^®; Nihon Kohden, Tokyo, Japan) was performed in patients with moderate-to-severe SDB who agreed to a further detailed examination of SDB during hospitalization. Polysomnography consisted of continuous recordings from 4 electroencephalographic leads, 2 electrooculography leads, and 3 electromyographic leads (1 submental and bilateral anterior tibialis); a nasal cannula with a pressure transducer and thermal sensor for nasal air flow; strain gauges for thoracic and abdominal movements; pulse oximetry; and ECG. Patients went to bed at their usual bedtime or before 9:00 pm, and the recording was terminated after 6:00 am. Apnea and hypopnea were defined according to the criteria of the American Academy of Sleep Medicine.²³ Apnea was defined as an absence of airflow for 10 s or longer and hypopnea as an airflow reduction (>50%) lasting 10 s or longer with a decrease in oxygen saturation of more than 3%. Obstructive apnea was defined as the absence of airflow in the presence of chest or abdominal wall motion. The apnea-hypopnea index (AHI) was calculated based on the average number of apnea plus hypopnea episodes per hour of sleep recording time.

When the AHI exceeded 20 events/h, patients were strongly recommended to try treatment with an autotitrating CPAP device (S9 AutoSet^TM; ResMed Ltd, Sydney, NSW, Australia) while asleep during hospitalization and after hospital discharge. Use of a CPAP device was also recommended for more than 4 h/night.²⁴ For patients who continued to use a CPAP device, fasting blood sampling and measurement of blood pressure were performed and the frequency of nocturnal urination was investigated at 3–6 months after the CPAP treatment was started. Data on CPAP usage (hours, rate of more than 4 h/night, and AHI) were downloaded from a smart card attached to the device. Favorable adherence to CPAP was defined as meeting the following criteria: “mean adherence of CPAP >4 h/night” and “adherence rate of CPAP >4 h/night in the previous 1 month >0.70”.²⁵ All patients were invited to visit the outpatient clinic for examination and to update medical information.

The study protocol was approved by the Human Ethics Review Committee of Kumamoto University and a signed consent form was given by each subject.

Statistical Analysis

All values are shown as the mean±standard deviation, and categorical variables are expressed as numbers and percentages. Continuous variables that did not show a normal distribution are expressed as the median value (25–75th percentile range). Continuous variables were compared using the t test or Mann-Whitney test, as appropriate. Categorical variables were analyzed by the chi-squared test or Fisher exact test, as appropriate. Linear relationships between key variables were determined using Pearson’s correlation coefficient. Variables with non-normal distribution were transformed logarithmically before a multiple logistic regression analysis to evaluate clinical variables that were significantly associated with nocturia. Statistical significance was defined as P<0.05. The analyses were performed using the SAS software package version 9.4 (SAS Institute, Inc, Cary, NC, USA).

Results

Of the 1,429 consecutive patients with CVD admitted to hospital, 850 fulfilled the inclusion criteria and 754 gave consent to participate in the study and underwent overnight monitoring with pulse oximetry. However, 88 patients were not enrolled because they underwent hemodialysis or had trouble with pulse oximetry. The study finally included 666 patients who were divided into 2 groups according to the presence of nocturia: 561 patients with nocturia (84%) and 105 patients (16%) without nocturia (Figure 1).

Figure 1.

Flow chart of recruitment to a study of cardiovascular disease patients with nocturia and sleep-disordered breathing.

Clinical Background and Factors Related to Nocturia

Table 1 shows the clinical characteristics of the patients with and without nocturia. There was a prevalence of men with nocturia. Patients with nocturia were significantly older and more obese than those without nocturia. They also had a higher incidence of coronary risk factors such as hypertension, diabetes mellitus, and dyslipidemia. They had lower arterial oxyhemoglobin saturation and showed the presence of anemia, chronic kidney disease, coronary heart disease, and high B-type natriuretic peptide (BNP) levels. Echocardiographic data demonstrated a significantly increased LV wall thickness and E/e’ ratio in the nocturia group, despite equivalent LV ejection fractions in the 2 groups. Regarding the nocturnal pulse oximetry data, oxygen saturation levels were lower in patients with nocturia and sleep time with saturation levels lower than 90% was longer than in patients without nocturia. They also had a higher 3%ODI and higher frequency of moderate-to-severe SDB (3%ODI >15 events/h) than those without nocturia (30.8% vs. 7.6%, P<0.0001) (Table 2). The frequency of nocturnal urination weakly but positively correlated with 3%ODI (Figure 2). A multiple logistic regression analysis was performed to identify the clinical factors related to nocturia. Nocturia was significantly associated with 3%ODI independent of age, male sex, hypertension, and BNP level (Table 3). Diuretics may affect nocturia. Diuretics were administered more frequently to the patients with nocturia than those without (20.0 vs. 8.6%, P=0.0055). However, diuretic administration was not significantly associated with nocturia, and other important variables were not affected even when diuretics were added as an independent variable, as shown in Table 3 (odds ratio 1.186 [95% confidence interval 0.499–2.818], P=0.6991).

Table 1. Baseline Characteristics of the CVD Patients Assessed for the Presence of Nocturia

Characteristic	Without nocturia (n=105)	With nocturia (n=561)	P value
Age, years	50.9±19.6	68.3±11.5	<0.0001
Male	53 (50.5)	354 (63.1)	0.0149
Height, cm	161.3±9.9	160.0±9.7	0.1907
Weight, kg	59.7±12.8	61.3±12.9	0.2501
Body mass index, kg/m²*	22.9±4.4	23.8±3.9	0.0287
Waist circumference, cm	85.2±12.5	88.3±11.0	0.0126
SpO₂ on admission, %^†	97.9±0.8	97.6±1.0	0.0062
Hemoglobin, g/dl	13.6±1.8	13.1±1.8	0.0092
Creatinine, mg/dl	0.75±0.24	0.91±0.39	<0.0001
Estimated glomerular filtration rate, ml/min/1.73 m²	83.4±25.4	65.0±19.9	<0.0001
Hypertension	41 (39.0)	422 (75.2)	<0.0001
Systolic blood pressure, mmHg	120.1±19.9	124.3±18.3	0.0328
Diastolic blood pressure, mmHg	71.1±14.3	70.1±12.1	0.4581
Diabetes mellitus	25 (23.8)	227 (40.5)	0.0012
Hemoglobin A_1c, %	5.9±0.9	6.2±1.1	0.0114
Dyslipidemia	64 (61.0)	433 (77.2)	0.0005
Triglycerides, mg/dl	105 (75–153)	105 (76–150)	0.9047
High-density lipoprotein cholesterol, mg/dl	55.2±16.7	52.1±14.9	0.0553
Low-density lipoprotein cholesterol, mg/dl	105.9±32.3	96.9±30.0	0.0058
B-type natriuretic peptide, pg/ml	15.2 (6.1–34.9)	44.5 (18.2–101.8)	<0.0001
Alcohol use	49 (46.7)	265 (47.2)	0.9144
Active smoking	18 (17.1)	57 (10.2)	0.0378
Prevalence of heart failure	10 (9.5)	78 (13.9)	0.2238
CVD
Coronary heart disease	21 (20.0)	225 (40.1)	<0.0001
Valvular heart disease	3 (2.9)	30 (5.3)	0.4595
Cardiomyopathy	8 (7.6)	49 (8.7)	0.7077
Atrial fibrillation/flutter	31 (29.5)	188 (33.5)	0.4247
Echocardiographic data
Interventricular septal thickness, mm	9.4±1.7	10.7±1.9	<0.0001
Posterior wall thickness, mm	9.4±1.5	10.5±1.8	<0.0001
Left ventriular diastolic diameter, mm	44.9±5.5	46.1±6.8	0.0866
Left ventricular ejection fraction, %	61.8±8.8	60.6±9.6	0.2244
E/e’	9.5±3.2	14.4±5.8	<0.0001

Data are mean±standard deviation, median (25–75^th percentiles), or number (percentage) of patients. *Body mass index is the weight in kilograms divided by the square of the height in meters. ^†Oxygen saturation level as measured by pulse oximetry. CVD, cardiovascular disease; SpO₂, oxygen saturation level as measured by pulse oximetry.

Table 2. Nocturnal Pulse Oximetry in CVD Patients Assessed for the Presence of Nocturia

Variable	Without nocturia (n=105)	With nocturia (n=561)	P value
SpO₂, %
Average	95.7±1.4	94.9±1.8	<0.0001
Nadir	82.9±8.2	80.4±7.4	0.0023
Sleep time with SpO₂ <90%, min	9.9±33.6	23.8±56.5	0.0153
Average pulse rate, /min	60.9±9.8	62.2±10.8	0.2562
3% oxygen desaturation index, events/h	7.3±8.7	12.4±10.3	<0.0001
Severity of SDB			<0.0001
Normal	56 (53.3)	128 (22.8)
Mild	41 (39.0)	260 (46.3)
Moderate	3 (2.9)	137 (24.4)
Severe	5 (4.8)	36 (6.4)

Values are mean±standard deviation or number (percentage) of patients. SDB, sleep-disordered breathing. Other abbreviations as in Table 1.

Figure 2.

Correlation between the frequency of nocturia and 3% oxygen desaturation index in cardiovascular disease patients with nocturia and sleep-disordered breathing.

Table 3. Independent Factors for Nocturia in Patients With CVD

Variable	OR (95% CI)	P value
Age (/10 years)	1.564 (1.255–1.949)	<0.0001
Male	2.295 (1.245–4.233)	0.0078
Waist circumference (/10 cm)	0.902 (0.704–1.155)	0.4127
SpO₂ on admission	0.946 (0.707–1.265)	0.7084
Hemoglobin	0.923 (0.764–1.115)	0.4058
Estimated glomerular filtration rate (/10 ml/min/1.73 m²)	0.906 (0.781–1.052)	0.1970
Hypertension	2.057 (1.158–3.656)	0.0139
Diabetes mellitus	0.875 (0.475–1.610)	0.6672
Dyslipidemia	0.836 (0.447–1.562)	0.5736
B-type natriuretic peptide (logarithmically transformed)	1.921 (1.116–3.308)	0.0185
Active smoking	0.622 (0.306–1.265)	0.1898
Coronary heart disease	1.651 (0.872–3.127)	0.1239
3% oxygen desaturation index (/10 events/h)	1.439 (1.029–2.014)	0.0335

CI, confidence interval; OR, odds ratio. Other abbreviations as in Table 1.

Assessment of AHI According to Polysomnography and Introduction of CPAP

Of the 666 patients included in the analysis, 181 had moderate-to-severe SDB and were recommended to undergo full-night polysomnography during hospitalization. However, it was not performed in 81 patients either because of a lack of consent or because their hospital stay was too short. Of the 100 patients who underwent polysomnography, 91 had an AHI ≥20 events/h. CPAP treatment was introduced for all 91 patients; however, 29 patients discontinued the treatment during hospitalization and did not take a CPAP device home. The remaining 62 patients took the device at discharge and continued to use it during sleep at home (Figure 3). They visited the outpatient clinic for examination and to update medical information 3–6 months after discharge. Blood sampling and blood pressure measurement were performed, and the frequency of nocturnal urination was investigated. A total of 32 patients continued to use a CPAP device for more than 3 months and both the use of the device and AHI was examined. The mean adherence to CPAP treatment was 4.2 (2.4–6.0) h/night and the rate of adherence to CPAP treatment >4 h/night in the previous month was 60.0% (23.3–93.0%); 30 patients stopped the CPAP treatment for at least 1 month before visiting the outpatient clinic.

Figure 3.

Full-night polysomnography and use of a continuous positive airway pressure device in the study group of cardiovascular disease patients with nocturia and sleep-disordered breathing.

Effect of CPAP on Nocturia

Patient who continued the CPAP treatment (n=32) showed a significant reduction in AHI during the treatment (2.5±3.7 events/h) from before the treatment (45.3±13.6 events/h, P<0.0001). Moreover, the frequency of nocturnal urination was significantly higher before treatment compared with during the treatment (Figure 4A). Moreover, there was a significant decrease in systolic blood pressure (SBP: 121.6±11.9 vs. 113.4±8.8 mmHg, P=0.0002) and BNP levels (57.7 [15.0–144.4] vs. 27.4 [8.5–111.7] pg/ml, P=0.0006). We also observed that 12 of 16 patients (75.0%) without nocturia in this group showed favorable adherence to the CPAP treatment, but only 4 patients of 16 patients with nocturia showed favorable adherence resulting from continuation of the CPAP treatment (25.0%, P=0.012). Moreover, 2 of those 4 patients had a low AHI (2.6 events/h each), and the number of nocturnal urinations was reduced by half (before treatment: 2 and 6 events/night; during treatment: 1 and 3 events/night; respectively). The remaining 2 patients had an AHI >10 events/h during the CPAP treatment (11.3 and 18.8 events/h, respectively), and the number of nocturnal urinations did not improve (before treatment: 4 and 5 events/night; during treatment: 4 and 5 events/night; respectively). Additionally, the frequency of nocturnal urination did not change in patients who discontinued the CPAP treatment (n=30) (Figure 4B). Moreover, there was no or only a slight increase in SBP (121.0±15.5 vs. 126.7±14.4 mmHg, P=0.018) and BNP levels (29.1 [20.6–62.7] vs. 37.9 [16.5–83.2] pg/ml, P=0.1425).

Figure 4.

Frequency of nocturnal urination in relation to continuation (A) or discontinuation (B) of continuous positive airway pressure (CPAP) therapy in cardiovascular disease patients with nocturia and sleep-disordered breathing.

Discussion

In the present study, nocturia was closely associated with SDB in patients with CVD. The severity of SDB positively correlated with the frequency of nocturia, whereas nocturia was closely associated with 3%ODI independent of age, male sex, hypertension, and BNP level. CPAP treatment resulted in a decrease in both the AHI and frequency of nocturia, and reduced frequency of nocturnal urination was associated with reduced SBP and BNP levels. Favorable adherence to the CPAP treatment resulted in resolution of nocturia in the majority of patients with CVD and OSA.

Patients with OSA experience repeated episodes of oxygen desaturation caused by transient cessation of breathing, which promotes systemic oxidative stress, inflammation, vascular endothelial dysfunction, insulin resistance, activated platelets, and hypercoagulability, in addition to increasing vascular sympathetic nerve activity and the levels of soluble cell adhesion molecules, adipokines, and catecholamines.²⁶^–³¹ This, in turn, may be strongly associated with future cardiovascular events, fatal arrhythmia and sudden cardiac death.⁵^,⁶^,⁸^,⁹^,²⁴^,³²^,³³ OSA is also a common sleep disorder associated with several adverse health outcomes,³⁴ and the sporadic night arousal characteristic of OSA is responsible for the nocturia.³⁵ In the present study, the severity of SDB correlated with the frequency of nocturnal urination; however, the mechanism of nocturia in patients with OSA has not been fully elucidated. Umlauf et al found that both nighttime urine production and atrial natriuretic peptide (ANP) excretion are elevated in SDB patients, and they proposed that the obstructive respiratory events generate negative intrathoracic pressure, causing the heart to receive a signal of volume overload.³⁶ The hormonal response to this signal is increased ANP secretion. Moreover, venous return to the right atrium is also increased, thereby causing distension of the right ventricle. The distension of the right side of the heart also produces a leftward shift of the interventricular septum, which impairs LV diastolic filling.³⁷ This implies a high E/e’ ratio, which may produce increased BNP levels. Increased secretion of natriuretic peptides may be associated with urinary production. These natriuretic peptides also inhibit the activity of the antidiuretic hormone, arginine vasopressin, and the renin-angiotensin-aldosterone system,³⁸ which may induce nocturnal urination, although arginine vasopressin levels and the activity of the renin-angiotensin-aldosterone system were not measured in the present study. In elderly people with nocturia, arginine vasopressin levels are low and do not increase nocturnally.³⁹^,⁴⁰ Furthermore, previous reports have shown that the levels of natriuretic peptides are closely associated with the severity of nocturia.³⁶^,⁴¹ Therefore, nocturia may be partly explained by hormonal imbalance during sleep in patients with OSA.

Nocturia is related to numerous potential risk factors, and the prevalence of nocturia increases with age; it is especially prevalent among elderly men.⁴² Nocturia is a symptom of an irritated lower urinary tract, and benign prostatic hyperplasia has been suggested as an etiological factor for these symptoms in men of an advanced age.⁴³^,⁴⁴ Therefore, the finding that age and male sex were independent factors in the present study suggests that benign prostatic hyperplasia is associated with nocturia. Our results also implicate SBP. Hypertension produces increased renal plasma flow, glomerular hyperfiltration, and impaired fractional sodium reabsorption, leading to nocturia.⁴⁵ An association has been demonstrated between a non-dipping pattern of hypertension and OSA.⁴⁶ Increasing sympathetic nerve activity caused by recurrent episodes of hypoxia and hypercapnia has been suggested as the possible mechanism underlying increased blood pressure during sleep.⁴⁷ Higher blood pressure is associated with more urine production at night and increased SBP is accompanied by decreased arginine vasopressin levels, which also increases nocturnal urine output.³⁹^,⁴⁰ Therefore, OSA may provide a link between hypertension and nocturia.

In the present study, the introduction of CPAP treatment improved nocturnal voiding, probably owing to normalization of oxygen desaturation caused by a significantly reduced AHI. Compared with patients who discontinued the treatment, those who completed it also showed blood pressure reduction and a decrease in BNP level. Thus, nocturia could be alleviated by weakening the effect of compounding factors related to nocturia in patients with OSA and CVD. This result shows that CPAP may be an attractive treatment with considerable potential for improving nocturia and other symptoms related to OSA.

OSA is an established cardiovascular risk factor, and treatment with a CPAP device reduces the frequency of fatal and nonfatal cardiovascular events in patients with severe OSA-hypopnea.²⁴ Nocturia is an independent predictor of mortality, especially in elderly patients.¹⁴^,³⁵ Moreover, elderly people who need to urinate many times per night have higher mortality rates associated with coronary disease.¹⁴ The present study showed that the therapeutic effect of CPAP on nocturia is satisfactory. Therefore, it is possible that nocturia could become a promising clinical sign for predicting future cardiovascular events in patients with OSA and CVD. Further investigation is needed to assess whether reduced frequency of nocturnal voiding is associated with reduced frequency of subsequent cardiovascular complications. However, our study showed that the presence of nocturia may be useful for identifying patients with SDB. Consequently, screening of patients with CVD complicated by SDB may require assessing the severity of SDB and administration of an adequate treatment for OSA, and the presence of nocturnal urination may have high clinical significance.

Study Limitations

First, it was limited to patients with CVD. Second, a pulse oximetry device was used at nighttime as a screening method, and we did not investigate any relationship between the ODI and AHI. However, previous studies reported that the ODI was useful in OSA because it closely correlated with the AHI and had potential for facilitating the accurate diagnosis of OSA with high sensitivity and specificity.⁴⁸^,⁴⁹ Moreover, a previous clinical study demonstrated that the cut-off value to predict an AHI of >5, >15, and >30 events/h with high accuracy was an ODI of >5, >15, and >30 events/h, respectively.⁵⁰ Third, patients were diagnosed with sleep apnea according to the AHI based on polysomnography, whereas the AHI during CPAP was extracted from a smart card attached to the device, and the 2 AHIs were compared: before and during CPAP treatment. However, a strong correlation between AHI determined by a CPAP device and AHI derived from polysomnography was previously reported.⁵¹ Therefore, the AHI determined by a CPAP device could be used rather than that derived from polysomnography, and the AHI during the CPAP treatment thus does not need to be determined by polysomnography. Fourth, it is widely acknowledged that nocturia has multiple etiologies such as nocturnal polyuria, bladder storage problem, and sleep disorder.¹³ This study was partly based on a questionnaire on the frequency of nocturnal urination, which is likely a disadvantage because a detailed frequency-volume chart was not used for each patient. However, OSA has been speculated to cause nocturia, and we demonstrated that CPAP treatment could reduce the frequency of nocturnal urination. Other treatments may be recommended if nocturia is not reduced, despite favorable adherence to CPAP treatment by patients with OSA and CVD.

In conclusion, nocturia is frequently observed in patients with CVD and SDB, as assessed by pulse oximetry. Our findings may help to explain the association between nocturia and SDB-related cardiovascular risks such as increased blood pressure and BNP levels. These risks and nocturia have been shown to be improved by CPAP treatment used for reducing the AHI, which may be beneficial for men of advanced age suffering from CVD and OSA.

Sources of Support

This work was supported in part by a Grant-in-Aid for Scientific Research (C-22590785) from the Ministry of Education, Science, and Culture, Japan, and Grants from Teijin Home Healthcare, Japan, and Fukuda Foundation for Medical Technology, Japan. There are no financial or other relationships that could lead to a conflict of interest.

Acknowledgments

The authors thank Aya Furusato, Aiki Kishi, and Komaki Yamaguchi for secretarial and technical assistance.

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