S l e e p a n d Bre a t h i n g i n C o n g e s t i v e H e a r t Fa i l u re David Rosen, MDa,*, Francoise Joelle Roux, MD, PhDb, Neomi Shah, MD, MPHa KEYWORDS Heart failure Sleep apnea Obstructive sleep apnea Central sleep apnea Cheyne-Stokes respiration Sleep-disordered breathing CPAP BPAP
KEY POINTS Sleep apnea is a common and underdiagnosed comorbidity of heart failure. Untreated sleep apnea is an independent risk factor for increased mortality in heart failure. Heart failure and sleep apnea are interrelated in that one disease can cause the other and vice versa. Noninvasive positive pressure ventilation is the mainstay of therapy for sleep apnea in heart failure.
Heart failure (HF) is one of the most prevalent and costly diseases in the United States.1 Sleep apnea (SA) is now recognized as a common, yet underdiagnosed, comorbidity of HF.2 Much investigation on the relationship between these two disorders has occurred already to help elucidate why they frequently occur together, what effect their coexistence has on patients’ morbidity and mortality, and how to best manage them when they coincide. This article discusses the unique qualities that SA has when it occurs in HF and explains the underlying pathophysiology that illuminates why SA and HF frequently occur together. The authors provide an overview of the treatment options for SA in HF and discuss the relative efficacies of these treatments. Of note, because of a paucity of data on SA in HF with preserved ejection fraction (HFpEF), the authors’ discussion of HF only refers to HF with reduced EF unless otherwise specified. In addition, the term SA is used as a broad term referring to any
of its subtypes, be it central SA (CSA), obstructive SA (OSA), or the occurrence of both together.
SLEEP CHARACTERISTICS IN HF WITHOUT SA Irrespective of the presence of a primary sleep disorder, nocturnal symptoms of HF alone can interfere with sleep quality. Cough is a wellestablished cause of sleep dysfunction3 and can be a manifestation of HF-related pulmonary edema. In addition, angiotensin-converting enzyme (ACE) inhibitors are a class I recommended medication for the treatment of HF4; 10% to 20% of patients treated with this medication will develop an ACE inhibitor–induced cough.5 Orthopnea and nocturia are common symptoms of HF, and they also cause sleep dysfunction. The effect of these symptoms on sleep quality was objectively measured by Javaheri6 in a single-center prospective study of patients with HF in whom polysomnography was obtained without screening for symptoms of SA. In the subset of patients with no SA (n 5 32, mean
a Pulmonary Medicine, Montefiore Medical Center, 111 E 210 Street, Bronx, NY 10467, USA; b Connecticut Multispecialty Group, Division of Pulmonary, Critical Care and Sleep Medicine, 85 Seymour Street, Suite 923, Hartford, CT 06106, USA * Corresponding author. 44 Godwin Avenue, Suite 201, Midland Park, NJ 07432. E-mail address: [email protected]
Clin Chest Med - (2014) -–http://dx.doi.org/10.1016/j.ccm.2014.06.008 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
2
Rosen et al apnea-hypopnea index [AHI] 5 2/h), the percentage of light sleep (N1) was elevated at 34% of the total sleep time. There was complete absence of deep sleep (N3, or slow wave sleep); the arousal index was elevated at 15/h. These patients also corroborated that the sleep measured on the night of their polysomnogram (PSG) was typical of a night’s sleep at home. In 2003, Arzt and colleagues7 compared polysomnography data in a HF cohort with a non-HF community sample cohort. In the subgroup of patients with HF with an AHI less than 5, they had statistically significantly increased sleep-onset latency and wake after sleep onset as compared with the control group. They also had significantly reduced rapid-eye-movement sleep and sleep efficiency, with an average of 1.2 hours less sleep per night.
DIAGNOSIS OF SA To diagnose SA, patients must undergo a PSG. It typically includes measurements of various activities during sleep, including heart rate, pulse oximetry, abdominal movement, chest wall movement, airflow through the nose and mouth, electroencephalographic activity, and leg movements. These measurements allow for the detection of hypoxemia during sleep and apneas and hypopneas, among other things. An apnea or hypopnea is defined as the complete or partial cessation of airflow for 10 seconds or more, respectively. Apneas and hypopneas are further characterized into central and obstructive subtypes. An obstructive apnea (OA) or hypopnea occurs when there is pharyngeal obstruction to airflow caused by collapse of the pharyngeal muscles at some point along the upper airway. The PSG will indicate persistent or increasing thoracoabdominal effort despite the lack of airflow. In contrast, a central apnea or hypopnea occurs when there is an absence or decrease of respiratory effort along with the cessation of airflow.8 The total number of apneas and hypopneas that occur during a PSG are added together and divided by the total amount of time patients slept during the PSG to give the AHI. The AHI indicates the average number of respiratory events that occur per hour. SA is diagnosed when there is an abnormally high AHI. An AHI less than 5 is normal, between 5 and 14 indicates mild SA, between 15 and 29 is moderate SA, and 30 or more is severe SA. When most of the respiratory events are caused by obstruction of airflow, the SA is called OSA. When most of the respiratory evens are caused by a lack of breath initiation, the SA is called CSA.8 AHI and hypoxemia are not only helpful in diagnosing and categorizing SA but their
resolution with therapy can help also objectively determine treatment response.
SA IN THE SETTING OF HF Epidemiology and Mortality of CSA in HF In the general population, CSA is rare in that its prevalence in the general population is less than 1%,9 which is starkly different than the prevalence of OSA. However, in the HF population, CSA prevalence can range from 21%10 to 37%.11 There is uncertainty as to whether CSA incurs a mortality risk in HF. There are several studies that argue for12,13 and against14,15 this assertion, though they are limited in that they are single centered with small sample sizes and there is no uniformity between them in how they diagnose CSA, define CSA, and in their inclusion/exclusion criteria (for example, whether patients with CSA on noninvasive positive pressure ventilation [NIPPV] are allowed in the study).16 Nevertheless, most studies indicate an independent association of CSA with increased mortality in HF.
CSA and Cheyne-Stokes Respiration in HF CSA is actually a broad term that encompasses several different disorders. The condition that causes CSA in patients with HF is called CheyneStokes respiration (CSR).17 It is a periodic breathing pattern whereby hyperpneic breaths gradually decrease into hypopneas and/or apneas in a crescendo-decrescendo fashion. This cycle of breathing periods lasts anywhere from 30 seconds to 2 minutes. CSR occurs in HF via several derangements to homeostatic processes. Pulmonary congestion will stimulate vagal nerve fibers in the alveolar wall called J receptors, which cause a hyperventilatory response.18 In addition, for reasons unknown, the apneic threshold remains close to the resting PCO2 in HF. Therefore, any slight decrease in PCO2 can bring it to less than the apneic threshold and cause an apnea. Once the apnea occurs, it continues until peripheral and central chemoreceptors can sense the PCO2 has returned to an appropriate level. As a result of reduced cardiac output, the circulation time is increased. Therefore, the peripheral and central PCO2 chemoreceptors incur a lag in sensing changes in PCO2.19 This lag partially explains why peripheral and central chemoreceptors will overshoot in their hyperventilatory response to a high PCO2 or undershoot their hypoventilatory response to a low PCO220 and, thus, perpetuate the cycle. Aside from J receptor stimulation, other events that may initiate the CSR cycle include hyperventilatory responses from hypoxemia21 or upper airway
Sleep and Breathing in Congestive Heart Failure obstruction22 or impaired diffusing capacity (Fig. 1).23
Epidemiology of OSA in HF OSA is exceedingly prevalent in the United States. It is estimated that among the Western population, 24% of men and 9% of women have SA.24 Among patients with HF, the prevalence of OSA was reported to be 11% in a study by Javaheri and colleagues,25 which consisted of 81 cardiology clinic patients who had an left ventricular EF (LVEF) less than 45%. In this study, the mean AHI in the OSA group was in the severe range (36 10 per hour). Patients with OSA tended to be heavier and had a higher prevalence of snoring compared with those without OSA. A subsequent study by Sin and colleagues26 consisted of a larger group of consecutive patients with congestive heart failure (CHF) (n 5 450; n 5 382 [85%] men) with a mean LVEF of 27.3 15.6%. Using an AHI cutoff of 10 per hour of sleep, the prevalence of OSA in this group was 37% (n 5 168). Similar to Javaheri’s study mentioned above25, the mean AHI for the OSA group was in the severe range. Like most patients with OSA, those with OSA and HF are heavier, snore frequently, and also are more likely to be men than women. Unlike most patients with OSA, excessive daytime sleepiness is not commonly reported in patients with OSA with HF. This finding suggests that OSA in HF may be less likely to present with sleepiness compared with OSA without HF.25 This point was further investigated by Arzt and colleagues27 when they compared patients with HF with those from a community sample, for any given severity of OSA. They
found that patients with OSA and HF have less total sleep time compared with patients with OSA without HF. Despite having shorter sleep duration, patients with OSA with HF had lower mean Epworth Sleepiness Scores for all categories of SA severity compared with patients with OSA without HF. They concluded that the lack of subjective sleepiness cannot be used as a consistent symptom for ruling out OSA in patients with HF. Besides clinic-based studies, there is evidence from population-based cohorts that also confirms an independent association between OSA and HF. As suggested by cross-sectional data from the Sleep Heart Health Study,28 OSA (defined as an AHI 11/h) was associated with a 2.38 relative increase in the likelihood of having HF after adjusting for confounding variables. Recently published prospective data from the sleep heart health study reported on the relationship between OSA and incident HF. A total of 1927 men and 2495 women aged 40 years and older and free of HF at baseline were followed for a mean duration of 8.7 years. In this study, men with severe OSA were 58% more likely to have incident HF than those with an AHI less than 5.29
Mortality in Patients with Coexisting OSA and HF Limited studies exist that have assessed the impact of OSA on mortality. Wang and colleagues30 conducted a prospective study of patients with HF (n 5 164, LVEF 45%). Each study participant underwent sleep testing, and the investigators assessed mortality in patients with untreated (AHI 15/h) and patients with mild
Fig. 1. Mechanism for initiation and perpetuation of CSR. DLCO, diffusing capacity of carbon monoxide.
3
4
Rosen et al or no OSA (AHI
KEY POINTS Sleep apnea is a common and underdiagnosed comorbidity of heart failure. Untreated sleep apnea is an independent risk factor for increased mortality in heart failure. Heart failure and sleep apnea are interrelated in that one disease can cause the other and vice versa. Noninvasive positive pressure ventilation is the mainstay of therapy for sleep apnea in heart failure.
Heart failure (HF) is one of the most prevalent and costly diseases in the United States.1 Sleep apnea (SA) is now recognized as a common, yet underdiagnosed, comorbidity of HF.2 Much investigation on the relationship between these two disorders has occurred already to help elucidate why they frequently occur together, what effect their coexistence has on patients’ morbidity and mortality, and how to best manage them when they coincide. This article discusses the unique qualities that SA has when it occurs in HF and explains the underlying pathophysiology that illuminates why SA and HF frequently occur together. The authors provide an overview of the treatment options for SA in HF and discuss the relative efficacies of these treatments. Of note, because of a paucity of data on SA in HF with preserved ejection fraction (HFpEF), the authors’ discussion of HF only refers to HF with reduced EF unless otherwise specified. In addition, the term SA is used as a broad term referring to any
of its subtypes, be it central SA (CSA), obstructive SA (OSA), or the occurrence of both together.
SLEEP CHARACTERISTICS IN HF WITHOUT SA Irrespective of the presence of a primary sleep disorder, nocturnal symptoms of HF alone can interfere with sleep quality. Cough is a wellestablished cause of sleep dysfunction3 and can be a manifestation of HF-related pulmonary edema. In addition, angiotensin-converting enzyme (ACE) inhibitors are a class I recommended medication for the treatment of HF4; 10% to 20% of patients treated with this medication will develop an ACE inhibitor–induced cough.5 Orthopnea and nocturia are common symptoms of HF, and they also cause sleep dysfunction. The effect of these symptoms on sleep quality was objectively measured by Javaheri6 in a single-center prospective study of patients with HF in whom polysomnography was obtained without screening for symptoms of SA. In the subset of patients with no SA (n 5 32, mean
a Pulmonary Medicine, Montefiore Medical Center, 111 E 210 Street, Bronx, NY 10467, USA; b Connecticut Multispecialty Group, Division of Pulmonary, Critical Care and Sleep Medicine, 85 Seymour Street, Suite 923, Hartford, CT 06106, USA * Corresponding author. 44 Godwin Avenue, Suite 201, Midland Park, NJ 07432. E-mail address: [email protected]
Clin Chest Med - (2014) -–http://dx.doi.org/10.1016/j.ccm.2014.06.008 0272-5231/14/$ – see front matter Ó 2014 Elsevier Inc. All rights reserved.
chestmed.theclinics.com
INTRODUCTION
2
Rosen et al apnea-hypopnea index [AHI] 5 2/h), the percentage of light sleep (N1) was elevated at 34% of the total sleep time. There was complete absence of deep sleep (N3, or slow wave sleep); the arousal index was elevated at 15/h. These patients also corroborated that the sleep measured on the night of their polysomnogram (PSG) was typical of a night’s sleep at home. In 2003, Arzt and colleagues7 compared polysomnography data in a HF cohort with a non-HF community sample cohort. In the subgroup of patients with HF with an AHI less than 5, they had statistically significantly increased sleep-onset latency and wake after sleep onset as compared with the control group. They also had significantly reduced rapid-eye-movement sleep and sleep efficiency, with an average of 1.2 hours less sleep per night.
DIAGNOSIS OF SA To diagnose SA, patients must undergo a PSG. It typically includes measurements of various activities during sleep, including heart rate, pulse oximetry, abdominal movement, chest wall movement, airflow through the nose and mouth, electroencephalographic activity, and leg movements. These measurements allow for the detection of hypoxemia during sleep and apneas and hypopneas, among other things. An apnea or hypopnea is defined as the complete or partial cessation of airflow for 10 seconds or more, respectively. Apneas and hypopneas are further characterized into central and obstructive subtypes. An obstructive apnea (OA) or hypopnea occurs when there is pharyngeal obstruction to airflow caused by collapse of the pharyngeal muscles at some point along the upper airway. The PSG will indicate persistent or increasing thoracoabdominal effort despite the lack of airflow. In contrast, a central apnea or hypopnea occurs when there is an absence or decrease of respiratory effort along with the cessation of airflow.8 The total number of apneas and hypopneas that occur during a PSG are added together and divided by the total amount of time patients slept during the PSG to give the AHI. The AHI indicates the average number of respiratory events that occur per hour. SA is diagnosed when there is an abnormally high AHI. An AHI less than 5 is normal, between 5 and 14 indicates mild SA, between 15 and 29 is moderate SA, and 30 or more is severe SA. When most of the respiratory events are caused by obstruction of airflow, the SA is called OSA. When most of the respiratory evens are caused by a lack of breath initiation, the SA is called CSA.8 AHI and hypoxemia are not only helpful in diagnosing and categorizing SA but their
resolution with therapy can help also objectively determine treatment response.
SA IN THE SETTING OF HF Epidemiology and Mortality of CSA in HF In the general population, CSA is rare in that its prevalence in the general population is less than 1%,9 which is starkly different than the prevalence of OSA. However, in the HF population, CSA prevalence can range from 21%10 to 37%.11 There is uncertainty as to whether CSA incurs a mortality risk in HF. There are several studies that argue for12,13 and against14,15 this assertion, though they are limited in that they are single centered with small sample sizes and there is no uniformity between them in how they diagnose CSA, define CSA, and in their inclusion/exclusion criteria (for example, whether patients with CSA on noninvasive positive pressure ventilation [NIPPV] are allowed in the study).16 Nevertheless, most studies indicate an independent association of CSA with increased mortality in HF.
CSA and Cheyne-Stokes Respiration in HF CSA is actually a broad term that encompasses several different disorders. The condition that causes CSA in patients with HF is called CheyneStokes respiration (CSR).17 It is a periodic breathing pattern whereby hyperpneic breaths gradually decrease into hypopneas and/or apneas in a crescendo-decrescendo fashion. This cycle of breathing periods lasts anywhere from 30 seconds to 2 minutes. CSR occurs in HF via several derangements to homeostatic processes. Pulmonary congestion will stimulate vagal nerve fibers in the alveolar wall called J receptors, which cause a hyperventilatory response.18 In addition, for reasons unknown, the apneic threshold remains close to the resting PCO2 in HF. Therefore, any slight decrease in PCO2 can bring it to less than the apneic threshold and cause an apnea. Once the apnea occurs, it continues until peripheral and central chemoreceptors can sense the PCO2 has returned to an appropriate level. As a result of reduced cardiac output, the circulation time is increased. Therefore, the peripheral and central PCO2 chemoreceptors incur a lag in sensing changes in PCO2.19 This lag partially explains why peripheral and central chemoreceptors will overshoot in their hyperventilatory response to a high PCO2 or undershoot their hypoventilatory response to a low PCO220 and, thus, perpetuate the cycle. Aside from J receptor stimulation, other events that may initiate the CSR cycle include hyperventilatory responses from hypoxemia21 or upper airway
Sleep and Breathing in Congestive Heart Failure obstruction22 or impaired diffusing capacity (Fig. 1).23
Epidemiology of OSA in HF OSA is exceedingly prevalent in the United States. It is estimated that among the Western population, 24% of men and 9% of women have SA.24 Among patients with HF, the prevalence of OSA was reported to be 11% in a study by Javaheri and colleagues,25 which consisted of 81 cardiology clinic patients who had an left ventricular EF (LVEF) less than 45%. In this study, the mean AHI in the OSA group was in the severe range (36 10 per hour). Patients with OSA tended to be heavier and had a higher prevalence of snoring compared with those without OSA. A subsequent study by Sin and colleagues26 consisted of a larger group of consecutive patients with congestive heart failure (CHF) (n 5 450; n 5 382 [85%] men) with a mean LVEF of 27.3 15.6%. Using an AHI cutoff of 10 per hour of sleep, the prevalence of OSA in this group was 37% (n 5 168). Similar to Javaheri’s study mentioned above25, the mean AHI for the OSA group was in the severe range. Like most patients with OSA, those with OSA and HF are heavier, snore frequently, and also are more likely to be men than women. Unlike most patients with OSA, excessive daytime sleepiness is not commonly reported in patients with OSA with HF. This finding suggests that OSA in HF may be less likely to present with sleepiness compared with OSA without HF.25 This point was further investigated by Arzt and colleagues27 when they compared patients with HF with those from a community sample, for any given severity of OSA. They
found that patients with OSA and HF have less total sleep time compared with patients with OSA without HF. Despite having shorter sleep duration, patients with OSA with HF had lower mean Epworth Sleepiness Scores for all categories of SA severity compared with patients with OSA without HF. They concluded that the lack of subjective sleepiness cannot be used as a consistent symptom for ruling out OSA in patients with HF. Besides clinic-based studies, there is evidence from population-based cohorts that also confirms an independent association between OSA and HF. As suggested by cross-sectional data from the Sleep Heart Health Study,28 OSA (defined as an AHI 11/h) was associated with a 2.38 relative increase in the likelihood of having HF after adjusting for confounding variables. Recently published prospective data from the sleep heart health study reported on the relationship between OSA and incident HF. A total of 1927 men and 2495 women aged 40 years and older and free of HF at baseline were followed for a mean duration of 8.7 years. In this study, men with severe OSA were 58% more likely to have incident HF than those with an AHI less than 5.29
Mortality in Patients with Coexisting OSA and HF Limited studies exist that have assessed the impact of OSA on mortality. Wang and colleagues30 conducted a prospective study of patients with HF (n 5 164, LVEF 45%). Each study participant underwent sleep testing, and the investigators assessed mortality in patients with untreated (AHI 15/h) and patients with mild
Fig. 1. Mechanism for initiation and perpetuation of CSR. DLCO, diffusing capacity of carbon monoxide.
3
4
Rosen et al or no OSA (AHI
