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Renal insufficiency, a common condition among patients with chronic heart failure, complicates the management of heart failure. However, the influence of renal insufficiency on sleep-disordered breathing (SDB) – another important comorbidity of heart failure – has not been well studied.
Seventy-nine patients (60 men and 19 women) with stable, symptomatic heart failure caused by left ventricular systolic dysfunction (left ventricular ejection fraction of less than 45%) were studied.
Thirty-nine patients (49%) had SDB as defined by an apnea-hypopnea index (AHI) of five or greater: 15 patients were classified as having mild SDB (AHI of five or greater and less than 15), 10 patients as having moderate SDB (AHI of 15 or greater and less than 30) and 14 patients as having severe SDB (AHI of 30 or greater). The etiology of SDB was predominantly central. Plasma brain natriuretic peptide concentration in the severe SDB group was 587±377 pg/mL, which was significantly higher than those of the remaining three groups (P<0.05). On the other hand, estimated glomerular filtration rate (eGFR) was comparable between non-SDB and SDB groups. There was no statistically significant correlation between eGFR and AHI, or between eGFR and the number of central sleep apneas in the study patients.
Higher plasma brain natriuretic peptide concentrations were associated with more severe SDB, whereas the level of eGFR was not correlated with the severity of SDB. The results suggest that renal dysfunction plays a relatively minor role in determining breathing abnormalities in chronic heart failure.
Sleep-disordered breathing (SDB) is highly prevalent in patients with chronic heart failure and is a therapeutic target to improve long-term outcomes of the syndrome (1). For example, continuous positive airway pressure ventilation improves not only quality of life but also survival in patients with both heart failure and SDB (2,3).
Recently, a pathophysiological interaction between cardiac and renal dysfunction (known as the cardiorenal syndrome) has attracted attention (4). Renal dysfunction exerts a direct impact on the long-term prognosis of patients with heart failure (5). Interestingly, renal insufficiency itself is a risk factor for SDB in patients without cardiac dysfunction (6,7). However, whether renal dysfunction has an influence on breathing abnormalities in patients with heart failure has not been investigated. Therefore, the aim of the present study was to determine whether plasma brain natriuretic peptide (BNP) concentration – a biomarker of cardiac dysfunction – and estimated glomerular filtration rate (eGFR) are associated with the severity of SDB in patients with symptomatic heart failure caused by left ventricular systolic dysfunction.
Seventy-nine patients (60 men and 19 women) with chronic heart failure caused by left ventricular systolic dysfunction were studied. All of the patients were symptomatic (New York Heart Association [NYHA] functional class II or III), had a left ventricular ejection fraction of less than 45% and were in a clinically stable condition for at least one month. The clinical characteristics of the study patients are summarized in Table 1. The study was conducted in accordance with hospital guidelines.
Renal function was evaluated by measuring eGFR, which was calculated using the revised Modification of Diet in Renal Disease (MDRD) equation for the Japanese population (8):
The severity of SDB was assessed by an overnight cardiorespiratory polygraph (Model FM-500, Fukuda Denshi, Japan), as previously reported (9). Briefly, the system recorded nasal airflow, chest/abdominal wall movements, oxygen saturation and electrocardiographic signals. Apnea was defined as the absence of airflow for 10 s or longer. Hypopnea was defined as an inspiratory airflow reduction of greater than 50% for 10 s or longer that is associated with a 3% or greater oxygen desaturation. Apnea-hypopnea index (AHI) was calculated as the average number of apnea and hypopnea episodes per hour during registration. An AHI threshold of five or greater was diagnostic for SDB. When associated with absent chest/abdominal movement, apnea was categorized as a central type. The diagnostic accuracy of the model used in the present study was previously reported (9).
Data are presented as mean ± SD. Comparisons of continuous variables between groups were performed by one-way ANOVA. P<0.05 was considered to be statistically significant.
Thirty-nine of 79 patients (49%) had an AHI of five or greater. These patients were further divided into three groups: 15 patients were classified as having mild SDB (AHI of five or greater and less than 15), 10 patients as having moderate SDB (AHI of 15 or greater and less than 30) and 14 patients as having severe SDB (AHI of 30 or greater). The number of obstructive and central apneas per night was, respectively, 3±6 and 9±10 in the non-SDB group, 8±8 and 66±21 in the mild SDB group, 27±36 and 157±43 in the moderate SDB group, and 17±16 and 307±52 in the severe SDB group (Figure 1). Thus, the etiology of SDB in the study patients was predominantly central. There was no statistically significant difference in age, body mass index, left ventricular ejection fraction or the prevalence of ischemic cardiomyopathy among the four groups (Table 2). Plasma BNP concentration in the severe SDB group was 587±377 pg/mL and was significantly higher than those of the remaining three groups (P<0.05).
The mean eGFR of the study patients was 54.1±24.1 mL/min/1.73 m2. The distribution of the patients with different eGFR ranges is shown in Figure 2. eGFR was comparable between the non-SDB and SDB groups (Table 2). There was no statistically significant correlation between eGFR and AHI, or between eGFR and the nightly number of central sleep apneas, in the study patients (Figure 3).
Approximately 50% of our patients with systolic heart failure had SDB as defined by an AHI of five or greater. We found that higher plasma BNP concentrations were associated with more severe SDB, whereas the levels of eGFR were not correlated with the severity of SDB. Thus, the data suggest that renal dysfunction plays a relatively minor role in determining breathing abnormalities in chronic heart failure.
Several earlier studies (1,2,10) have found SDB to be highly prevalent in patients with cardiac dysfunction, and attempts have also been made to identify clinical risk factors for SDB. For example, Sin et al (10) found that age was a risk factor for central sleep apnea in both male and female heart failure patients. However, whether the severity of SDB is directly related to that of heart failure is not well understood. Thus, we aimed to determine whether plasma BNP concentration, which is among the clinical indicators for assessing heart failure severity, is correlated with AHI. Carmona-Bernal et al (11) previously reported that there was a positive correlation between BNP levels and AHI in 90 patients with a relatively mild form of heart failure. However, the majority of their patients were in NYHA class I or II, whereas approximately 40% of our patients were in NYHA class III. Furthermore, in the study by Carmona-Bernal et al (11), mean BNP concentrations were 62.0 pg/mL in the non-SDB group and 166.4 pg/mL in the SDB group, which were much lower than those of our patients. Thus, the present analysis confirms a positive correlation between BNP levels and SDB severity in patients with more severe heart failure status. A similar result was recently reported by other investigators (12).
Whether the relationship between BNP concentration and SDB simply represents unrelated expressions of a deteriorated cardiac function, or whether there is a direct causal relationship between BNP concentration and SDB, is unknown. Repetitive nocturnal apneas cause arterial deoxygenation associated with neurohumoral activation (shown by elevated plasma/urine catecholamine levels) (12,13), and reoxygenation following hypoxemia may increase oxygen radical formation (14). These neurohumoral alterations may directly or indirectly increase ventricular wall stress and BNP production. Within this context, Pepperell et al (15) reported that continuous positive airway pressure not only ameliorated abnormal breathing but also decreased BNP concentration, which may support the notion that SDB is causatively related to elevated BNP concentrations.
Impaired renal function is another important comorbidity of heart failure and is an independent risk factor for poor prognosis of the disease (5). Intriguingly, renal insufficiency itself is reported to be associated with the risk of breathing abnormalities in selected patients without heart disease (6,7,16). In the present study, the values of eGFR were comparable among the four groups classified according to the severity of SDB. In addition, no correlation was found between eGFR and the number of central apneic episodes. Thus, we believe that renal insufficiency plays a minor role in determining the severity of SDB in heart failure. Several investigators reported that SDB was common (53% to 75%) in patients with end-stage renal disease and no cardiac dysfunction. In contrast, there is still controversy regarding the prevalence of SDB in nondialysis patients (7,17). Possible contributing factors to the disturbance of sleep regulation in patients with renal insufficiency include metabolic acidosis, anemia, associated cardiovascular comorbidities, endogenous opioids and uremic neuropathy (18). In this context, end-stage renal failure was not common in our patients. Only three patients (3.8%) had an eGFR of less than 15 mL/min/1.73 m2, and none of the patients were undergoing dialysis. However, the present cohort of patients with symptomatic, chronic heart failure had a similar distribution of eGFR values compared with those of a larger cohort of heart failure patients (5,19); it is possible that the results of the present study could be extrapolated to the general population.
The severity of heart failure, as evaluated by plasma BNP concentrations, appears to be more closely correlated with SDB than renal insufficiency in symptomatic, but stable, heart failure patients with left ventricular systolic dysfunction. The mechanism by which renal failure affects the long-term outcomes of heart failure in this patient population may not be directly attributable to the breathing disturbances during sleep.
CONFLICTS OF INTEREST: The authors have no conflicts of interest to declare.