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(Chest. 2007;131:130-135.)
© 2007 American College of Chest Physicians

Relationship Between ß-Blocker Treatment and the Severity of Central Sleep Apnea in Chronic Heart Failure*

Akira Tamura, MD; Yoshiyuki Kawano, MD; Shigeru Naono, MD; Munenori Kotoku, MD and Jun-ichi Kadota, MD, PhD

* From the Second Department of Internal Medicine, Faculty of Medicine, Oita University, Oita, Japan.

Correspondence to: Akira Tamura, MD, Second Department of Internal Medicine, Faculty of Medicine, Oita University, Hasama, Yufu, Oita 879-5593, Japan; e-mail: akira{at}med.oita-u.ac.jp

Abstract

Background: We sought to examine the relationship between use of ß-blockers and the severity of central sleep apnea (CSA) in patients with chronic heart failure.

Methods: We performed polysomnography in 45 patients with chronic heart failure (New York Heart Association functional class II/III and left ventricular ejection fraction < 50%) and examined the relationship between use of ß-blockers and the severity of CSA. Central apnea index (CAI) was used as an indicator of CSA.

Results: Patients receiving ß-blockers (ie, carvedilol; n = 27) had lower apnea-hypopnea index (AHI) and CAI than patients not receiving ß-blockers (n = 18) [mean ± SD, 14 ± 11 vs 33 ± 17, p < 0.0001; and 1.9 ± 3.2 vs 11 ± 12, p = 0.0004, respectively]. AHI and CAI were negatively correlated with the dose of carvedilol (Spearman {rho} = – 0.61, p < 0.0001; and Spearman {rho} = – 0.57, p = 0.0002, respectively). Multiple regression analysis selected no use of ß-blockers as an independent factor of CAI (p = 0.0006). In five patients with CAI > 5 who underwent serial sleep studies, CAI decreased significantly after 6 months of treatment with carvedilol (9.5 ± 4.9 to 1.3 ± 2.4, p = 0.03).

Conclusions: In patients with chronic heart failure, CAI was lower according to the dose of ß-blockers, and no use of ß-blockers was independently associated with CAI. In addition, 6 months of treatment with carvedilol decreased CAI. These results suggest that ß-blocker therapy may dose-dependently suppress CSA in patients with chronic heart failure.

Key Words: ß-blocker • central sleep apnea • chronic heart failure

Previous epidemiologic studies1234 have shown that 30 to 50% of patients with chronic heart failure due to left ventricular systolic dysfunction have central sleep apnea (CSA). CSA has been shown to be associated with increased mortality in patients with chronic heart failure.5678 The following mechanisms responsible for the initiation and maintenance of CSA in chronic heart failure have been proposed: enhanced central and peripheral chemosensitivity to CO2910; prolonged circulation time, which produces a time delay between changes in blood gas tensions in the lung and their detection in the chemoreceptors1112; and stimulation of pulmonary vagal irritant receptors by pulmonary congestion.13141516 It has been believed that enhanced central chemosensitivity to CO2 is a major determinant of CSA in chronic heart failure,8 and it has been shown that activation of the sympathetic nervous system, which is observed in severe chronic heart failure, results in enhanced central chemosensitivity to CO2.171819202122 Therefore, ß-blocker therapy may reduce the severity of CSA in patients with chronic heart failure. In this study, we examined the relationship between use of ß-blockers and the severity of CSA in patients with chronic heart failure.

Materials and Methods

Patients
Between January 2004 and May 2005, 45 consecutive patients (31 men and 14 women; mean age ± SD, 64 ± 13 years) with chronic heart failure who were admitted to our hospital and who met the following criteria were enrolled into this study. Inclusion criteria were chronic heart failure with New York Heart Association (NYHA) functional class II or III and left ventricular ejection fraction (LVEF) < 50%. Exclusion criteria were previous cerebrovascular disease, recent (< 6 months) acute coronary syndrome, or chronic respiratory disease. The reasons for admission to our hospital were a diagnosis of underlying heart disease together with the induction of ß-blockers (n = 14) and sleep studies (n = 31). The etiology of chronic heart failure was idiopathic dilated cardiomyopathy in 25 patients and previous myocardial infarction in 20 patients. The study protocol was approved by the ethics committee at our institution, and informed consent was obtained from each patient before the study.

Polysomnography
Overnight polysomnography was performed using a computerized system (E-series; Compumedics Limited; Abbotsford, Australia). This investigation consisted of monitoring of the EEG, electrooculogram, submental electromyogram, ECG, thoracoabdominal excursions, oronasal airflow by an airflow pressure transducer, and arterial oxygen saturation by pulse oximetry. A central apnea was defined as an absence of oronasal airflow during sleep for ≥ 10 s associated with absent respiratory effort. An obstructive apnea was defined as an absence of oronasal airflow for ≥ 10 s in the presence of out-of-phase thoracoabdominal effort. Hypopnea was defined as a ≥ 50% reduction in oronasal airflow for ≥ 10 s associated with a ≥ 3% fall in oxygen saturation. The apnea-hypopnea index (AHI) was calculated as the mean number of apneas and hypopneas per hour of sleep. Also, the central apnea index (CAI) or obstructive apnea index (OAI) were calculated as the mean number of central or obstructive apneas, respectively. As a central hypopnea cannot be easily distinguished from an obstructive hypopnea, CAI was used as an indicator of CSA.

Echocardiography
Echocardiography was performed using standard techniques with an ultrasound system (model SSD-5500; Aloka; Tokyo, Japan). LVEF was calculated using a modification of the Simpson rule.23

Measurements of Plasma Brain Natriuretic Peptide Levels
Plasma brain natriuretic peptide (BNP) levels were measured using a specific immunoradiometric assay for human BNP (Shinoria BNP kit; Shionogi; Osaka, Japan).

Statistical Analysis
Continuous variables are expressed as mean ± SD and were analyzed by the Mann-Whitney U test or paired t test. Categorical data were analyzed using Fisher exact test or {chi}2 test. Spearman correlation analysis was performed to estimate correlations between AHI or CAI and the dose of carvedilol or plasma BNP levels. Multiple regression analysis was performed to determine factors related to CAI. The variables used for the analysis were age, gender, body mass index, etiology of chronic heart failure, NYHA functional class, LVEF, BNP levels, PaO2, PaCO2, use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs), and use of ß-blockers. A p value < 0.05 was considered statistically significant.

Results

Clinical characteristics of patients studied are shown in Table 1 . The ß-blocker administered was carvedilol. Of 18 patients not receiving ß-blockers, 14 patients received ß-blockers at a later time, and 4 patients were not treated with ß-blockers because of hypotension and bradycardia. Patients receiving ß-blocker treatment (n = 27) had lower AHI and CAI than those not receiving ß-blocker treatment (n = 18) [14 ± 11 vs 33 ± 17, p < 0.0001; and 1.9 ± 3.2 vs 11 ± 12, p = 0.0004, respectively]. There were no significant differences in age, gender, body mass index, etiology of chronic heart failure, NYHA functional class, LVEF, BNP levels, PaO2, PaCO2, OAI, and use of other cardiovascular drugs between patients with and without ß-blocker treatment.


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  		Table 1.. Patient Characteristics*

 
The dose of carvedilol was negatively correlated with AHI (Spearman {rho} = – 0.61, p < 0.0001) and CAI (Spearman {rho} = – 0.57, p = 0.0002) [Fig 1 ]. No patients who were treated with ≥ 10 mg/d of carvedilol had CAI > 5. Plasma BNP levels were positively correlated with CAI (Spearman {rho} = 0.30, p = 0.047) but not with AHI (Spearman {rho} = 0.21, p = 0.18) [Fig 2 ]. Multiple regression analysis selected no use of ß-blockers as an independent factor of CAI (p = 0.0006) [Table 2 ].


Figure 1
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  		Figure 1.. The relationship between the dose of ß-blocker (ie, carvedilol) and AHI or CAI.

 

Figure 2
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  		Figure 2.. The relationship between plasma BNP levels and AHI or CAI.

 

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  		Table 2.. Multiple Regression Analysis To Determine Factors Related to CAI

 
Five patients (four men and one woman; mean age, 72 ± 5.1 years) with CAI > 5 underwent polysomnography 6 months after the induction of carvedilol. After treatment with carvedilol, AHI and CAI decreased significantly (28.8 ± 7.5 to 12.4 ± 9.1, p = 0.02; and 9.5 ± 4.9 to 1.3 ± 2.4, p = 0.03, respectively) [Fig 3 ]. However, OAI did not change significantly (1.8 ± 1.4 to 1.4 ± 1.5, p = 0.54).


Figure 3
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  		Figure 3.. Changes in AHI and CAI before and 6 months after induction of carvedilol in five patients with CAI > 5 at baseline.

 
Discussion

The major findings of the present study are as follows: (1) patients with chronic heart failure receiving ß-blocker therapy had lower AHI and CAI than patients not receiving ß-blocker therapy; (2) the dose of carvedilol was negatively correlated with AHI and CAI; (3) the multiple regression analysis selected no use of ß-blockers as an independent factor of CAI; and (4) 6 months of treatment with carvedilol decreased CAI in five patients with CAI > 5 who underwent serial sleep studies. These results suggest that ß-blocker therapy may dose-dependently reduce the severity of CSA in patients with chronic heart failure.

Enhanced central chemosensitivity to CO2 could destabilize breathing during sleep. When PaCO2 rises during sleep in persons with increased central chemosensitivity to CO2, the negative-feedback system that controls breathing would elicit a large ventilatory response and lower PaCO2 below the apneic threshold, thereby resulting in CSA. Javaheri9 demonstrated that chronic heart failure patients with CSA have a significantly greater central chemosensitivity to CO2 than those without CSA, and that there is a significant positive correlation between central chemosensitivity to CO2 and AHI, concluding that enhanced central chemosensitivity to CO2 plays a major role in the genesis of CSA in chronic heart failure. Solin et al10 demonstrated that enhanced peripheral chemosensitivity to CO2 also contributes to the genesis of CSA in chronic heart failure patients, although it is generally believed that enhanced central chemosensitivity to CO2 has the larger role in the genesis of CSA. Endogenous catecholamines can increase the responsiveness of the respiratory controller to CO2, leading to hyperventilation.17181920 Yamada et al21 demonstrated that there is a significant positive correlation between enhanced central chemosensitivity to CO2 and plasma norepinephrine levels in patients with chronic heart failure, and that inhibition of central sympathetic neural outflow reduces plasma norepinephrine levels and suppresses enhanced central chemosensitivity to CO2. Moreover, Takahashi et al22 demonstrated that IV administration of isoproterenol significantly increases central chemosensitivity of CO2 in healthy volunteers and that IV administration of propranolol significantly decreases central chemosensitivity to CO2. These results indicate that activated sympathetic nervous system enhances central chemosensitivity to CO2. Therefore, ß-blocker therapy can reduce the severity of CSA in patients with chronic heart failure through restoration of enhanced central chemosensitivity to CO2.

Prolonged circulation time between lungs and chemoreceptors1112 and stimulation of pulmonary vagal irritant receptors caused by pulmonary congestion,13141516 which occur in severe chronic heart failure, have been shown to contribute to the genesis of CSA in patients with chronic heart failure. Therefore, improvement in cardiac function can reduce the severity of CSA. Indeed, Sinha et al24 demonstrated that cardiac resynchronization therapy improves cardiac function in patients with chronic heart failure, resulting in reducing the severity of CSA. ß-Blocker therapy may reduce the severity of CSA by improvement in cardiac function through several mechanisms such as heart rate reduction, favorable effects on myocardial energetics, and prevention of adrenergically mediated myocardial dysfunction.2526

It has been believed that CSA is related to the severity of chronic heart failure.2 Although several studies2327 have shown that CSA is related to low LVEF in patients with chronic heart failure, the correlation between AHI and LVEF was weak. Moreover, some studies428 have shown that CSA is not related to LVEF in patients with chronic heart failure. In the present study, CAI did not correlate with LVEF. Plasma BNP level has been shown to be superior to LVEF in identifying chronic heart failure patients who have a poor prognosis.2930 Carmona-Bernal et al31 recently demonstrated a weak but significant correlation between AHI and BNP levels in chronic heart failure patients. CSA may increase BNP levels through hypoxia and activation of the sympathetic nervous system. Alternatively, this relationship may be because the presence of CSA is an index of more severe chronic heart failure. The present study showed a marginal relationship between plasma BNP levels and CAI. The relationship between the severity of CSA and plasma BNP levels remains to be investigated.

Several studies42732 have shown that CSA is related to low awake PaCO2 in patients with chronic heart failure. In the present study, CAI had a tendency toward a negative correlation with awake PaCO2. However, although a low awake PaCO2 is highly predictive of CSA, it is not a prerequisite, and many chronic heart failure patients with CSA have normal awake PaCO2.28

Previous studies5678 have shown that CSA is associated with increased mortality in patients with chronic heart failure. However, in those days when those studies were performed, the frequency of use of ß-blockers was low in patients with CHF. Considering the results of the present study and beneficial effects of ß-blocker therapy on mortality in chronic heart failure,33 widespread use of ß-blockers may modify the prevalence and prognostic significance of CSA in patients with chronic heart failure. The impact of ß-blockers on CSA remains to be clarified in patients with chronic heart failure.

The present study has certain limitations. First, a sample size was small. In particular, the number of CSA patients in whom we could assess the severity of CSA before and after the induction of carvedilol was only five. Therefore, further studies with a large population are needed to confirm our results. Second, we did not measure central chemosensitivity to CO2. Therefore, further studies are needed to clarify whether oral administration of ß-blockers indeed suppresses central chemosensitivity to CO2 in patients with chronic heart failure, leading to reduce the severity of CSA.

In conclusion, CAI was lower according to the dose of ß-blockers in chronic heart failure patients, and no use of ß-blockers was independently associated with CAI. In addition, 6 months of treatment with carvedilol decreased CAI in five patients with CAI > 5 who underwent serial sleep studies. These results suggest that ß-blocker therapy may dose-dependently suppress CSA in patients with chronic heart failure.

Footnotes

Abbreviations: ACEI = angiotensin-converting enzyme inhibitor; AHI = apnea-hypopnea index; ARB = angiotensin II receptor blocker; BNP = brain natriuretic peptide; CAI = central apnea index; CSA = central sleep apnea; LVEF = left ventricular ejection fraction; NYHA = New York Heart Association; OAI = obstructive apnea index

None of the authors have any conflicts of interest to disclose.

Received for publication April 6, 2006. Accepted for publication July 24, 2006.

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