Introduction

Sleep disordered breathing includes obstructive sleep apnea (OSA), central sleep apnea (CSA) and sleep associated hypoventilation. This discussion is limited to OSA and CSA which involve almost one billion individuals throughout the world, including 40 million Americans. ^, Within the United States, the National Commission on Sleep Disorders Research estimates that sleep apnea is responsible for 42 million dollars spent for hospital diagnosis and treatment and for 38,000 cardiovascular deaths each year. Of major medical concern is the fact that the prevalence of sleep disordered breathing is significantly increasing due to the epidemic of obesity, inactivity, and diabetes mellitus which are important risk factors for the development and persistence of sleep apnea and sleep associated hypoventilation.

Sleep disordered breathing is characterized by multiple episodes of apneas and hypopnea during sleep, which causes nocturnal arousals, gasping for breath during the night, daytime sleepiness, irritability, forgetfulness, fatigue and recurrent headaches. An apneic episode is the absence or greater than 90% reduction of inspiratory airflow for at least 10 seconds. A hypopnea episode is a slow, shallow, restricted breathing with greater than 30% reduction of airflow that occurs for 10 seconds or longer, repeatedly during sleep. Prolonged or repeated apneas or hypopneas during sleep are associated with a decreased in the arterial oxyhemoglobin saturation (SpO2) of ≥3%.

The severity of sleep disordered breathing (SDB) is measured by the Apnea–Hypopnea Index (AHI), the Respiratory Disturbance Index (RDI), or the Respiratory Event Index (REI). The AHI is the average number of apneas and hypopneas per hour of sleep measured by polysomnography. The RDI is the total number of apneas, hypopneas, and the respiratory effort related arousals per hour of sleep during polysomnography. The REI is the number of apneas and hypopneas per hour of total recording time measured by a monitoring device during presumed sleep (as sleep is not measured) at home or elsewhere. The most common measurement of total OSA and CSA is the AHI. OSA is mild if the AHI is 5-14 events/hour with no or mild symptoms, moderate if the AHI is 15 to 30 events/hour usually with occasional daytime sleepiness, or severe if the AHI is >30 events/hour often associated with frequent daytime sleepiness that interferes with normal activities of daily life.

Apneas and hypopneas followed by compensatory hyperpneas are associated with acute adverse cardiovascular consequences including: 1) Intermittent hypoxemia and fluctuations in the arterial carbon dioxide concentration; 2) Increased sympathetic nerve activity and decreased parasympathetic nerve activity; 3) oxidative stress and vascular endothelial dysfunction; and 4) cardiac remodeling and cardiovascular disease. These adverse cardiovascular consequences of moderate or severe sleep disordered breathing increase the risk of cardiovascular abnormalities and cardiovascular mortality including :

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  Coronary Artery Disease

  
  
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  Congestive Heart Failure

  
  
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  Cardiac Dysrhythmias

  
  
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  Cerebral Vascular Events (Strokes).

Nevertheless, sleep apnea is currently underdiagnosed and untreated in many individuals due to the challenges in the prediction and detection of sleep apnea, and a lack of well-defined optimal treatment guidelines.

Sleep apnea diagnosis

There are three types of sleep apnea: obstructive sleep apnea, central sleep apnea and complex apnea. Obstructive apnea occurs when upper airway obstruction occurs in an individual during sleep with absent or markedly reduced airflow in the presence of continued activity of inspiratory intercostal and diaphragmatic muscles. In contrast, central sleep apnea occurs when there is a transient absence or reduction of respiratory muscle nerve stimulation by the ponto-medullary respiratory centers in the brain in the generation of breathing rhythm and airflow, usually due to reductions in the partial pressure of CO2 which falls below a level of PCO2 where breathing ceases, i.e. the apneic threshold. Complex sleep apnea occurs when an individual exhibits characteristics of both obstructive and central sleep apnea. The most common sleep apnea is OSA.

Obstructive sleep apnea

The overall prevalence of obstructive sleep apnea (OSA) in the general population is 9 to 38% and varies with the body mass index, sex, age and the AHI definitions used for diagnosis. Obesity is the most strongly predictive risk factor for OSA. In addition, the prevalence of OSA increases approximately 17- fold as people age from young adulthood to approximately 60–65 years. The incidence of sleep apnea in women increases after menopause due to decreases in body estrogen and progesterone concentrations which impact on weight gain and pharyngeal fat deposits with pharyngeal narrowing. In addition, women who are pregnant or who have polycystic ovarian syndrome also have increased incidences of OSA due to their weight gain and hormonal fluctuations. Obstructive sleep apnea results commonly from fat deposition in the neck and pharyngeal area that restricts airflow during sleep and also from posterior displacement of the tongue during sleep with obstruction of the upper airway. ^{, ,}

Twenty to 40% of OSA patients, however, are not obese. In these individuals OSA may result from anatomical factors that can obstruct the upper airway such as significant enlargement of the tongue, a long soft palate, a decreased mandibular or maxillary length, pharyngeal neuropathy, rostral fluid shift from the legs to the neck during sleep, or from non-anatomic factors, such as decreased PCO2 chemosensitivity, and decreased arousal threshold during hypoxemia. ^,

The OSA syndrome is characterized by recurring events of partial or complete upper airway obstruction during sleep, resulting in decreased alveolar ventilation, intermittent hypoxemia and hypercarbia associated with increased respiratory efforts of the intercostal muscles and diaphragm and intra-thoracic negative pressure swings that frequently lead to patient arousal and fragmented sleep. The International Classification of Sleep Disorders defines OSA as the presence of symptoms or certain comorbidities associated with five or more predominantly obstructive respiratory events per hour or in asymptomatic individuals by 15 or more predominantly obstructive respiratory events per hour.

Symptoms of OSA include loud snoring, frequent nocturnal waking due to gasping or choking, dry mouth, nocturia, morning headaches, poor concentration during the day, daytime sleepiness and fatigue, irritability, and male erectile dysfunction. Symptoms often reported by women include insomnia, impaired memory, and mood disturbances.

The physical examination of the patient with OSA may demonstrate central obesity with increased waist and neck circumference, nasal septal deviation or turbinate hypertrophy, micrognathia, soft palate elongation, macroglossia, and crowding of the posterior oropharynx due to tonsillar enlargement, or dental malocclusion. Signs indicative of pharyngeal obstruction include the presence of snoring indicating a flow-limited upper airway obstruction, a thoracoabdominal paradox with inward motion of the ribcage in concert with outward motion of the abdomen indicative of increased respiratory system resistance, or flattening or scooping of the inspiratory flow loop during pulmonary function testing.

Fig. 1 lists the diagnostic criteria for OSA defined by the American Academy of Sleep Medicine. Fig. 1 is adapted in part from References. ^,

Diagnosis of OSA.

An estimated 1 in 5 adults have at least mild OSA and 1 in 15 have at least moderate OSA. Polysomnography is the gold standard for diagnosis of OSA. Polysomnography often includes an electroencephalogram for monitoring sleep staging, arousals, and abnormal seizure activity, an electrooculogram for recording horizontal and vertical eye movements, electromyograms for recording chin muscle tone and periodic leg movements, respiratory channels for recording airflow, respiratory rate/effort and oxygen saturation (SpO2) measurements, and an electrocardiogram for recording heart rhythm. ^, Home sleep apnea testing can be used in patients with a high pretest probability of OSA but without clinical cardiopulmonary comorbidity. However, 17% of the portable OSA tests are false negatives that are often due to poor sleep and up to 18% have technical measurement failures. Consequently, if the results of the portable testing are negative in an individual for whom there is a high index of suspicion of OSA, additional polysomnography in an accredited facility should be performed. Fig. 2 is a polysomnographic record of an individual with OSA and is adapted, in part, from Reference.

Polysomnography of a patient with obstructive sleep Apnea.

Note in Fig. 2 , the intermittent absence of airflow with obstruction of the upper airway. This is associated with increases in blood pressure and heart rate, and attempts by the thoracic and diaphragmatic muscles to cause airflow. The SpO2 is measured by pulse oximetry usually at the fingertip and the signal is delayed relative to the apnea due to lung-to-finger circulation time. Arousals as noted on the electroencephalogram terminate the obstructive events, with resumption of breathing and restoration of oxygen saturation to normal concentrations.

Central sleep apnea

Central sleep apnea (CSA) is defined as the absence or the significant reduction of naso-oral airflow due to the withdrawal during sleep of ponto-medullary respiratory center stimulation to the nerves of the inspiratory thoracic and diaphragmatic muscles and absence of contraction of these muscles during apnea. The gold standard for the specific diagnosis of CSA is polysomnography with ≥ 5 events of central apnea or hypopneas per hour of sleep with the number of central apneas and/or hypopneas > 50% of the total number of apneas and hypopneas since CSA can occur with obstructive sleep apnea. Central sleep apnea or hypopneas are usually associated with modest decreases in SpO2 with the SpO2 rarely falling below 80 to 85% saturation.

Ventilatory instability is the most widely accepted mechanism leading to CSA in individuals and can be due to increased sensitivity of the ponto-medullary respiratory centers in the brainstem to small changes in CO2. ^{, ,} Individuals with CSA tend to hyperventilate in response to small increases in PaCO2. Apnea occurs when the PaCO2 decreases below an individual’s apneic threshold, which is 2 to 6 mmHg below the sleeping PaCO2. The ponto-medullary ventilatory stimulation output stops, thereby silencing motor nerves innervating the inspiratory muscles. Ventilation ceases and apnea persists until PaCO2 rises above the apneic threshold. ^, As the CO2 increases, patient arousal and hyperventilation occur and the cycle of apnea/hypopnea alternating with hyperpnea recurs.

The cessation of ventilatory motor output with CSA initiates a cascade of events that perpetuate unstable breathing including hypoxia, hypercapnia, sympathetic excitation, frequent post-apneic arousals from sleep, surges in ventilatory drive with hyperpnea, and fluctuations in systemic blood pressure. Patients with CSA report frequent awakening with shortness of breath during the night and difficulty sleeping.

Polysomnography and not portable sleep testing is necessary in order to properly differentiate CSA from OSA. Fig. 3 shows the polysomnographic record of an individual with CSA and is adapted in part from Reference. Note in Fig. 3 the lack of thoracic and diaphragmatic muscle movement during the absent airflow. This is associated with an increase in blood pressure and EEG electrical activity with patient arousal.

Polysomnography of a patient with central sleep Apnea.

The following forms of CSA can occur: ^{, ,}

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  Primary (idiopathic) central sleep apnea

  
  
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  Central sleep apnea with Cheyne-Stokes breathing

  
  
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  Central sleep apnea due a medical disorders (Hypothyroidism, Renal Failure) or neuromuscular disorders (Parkinson’s disease, Alzheimer’s disease, Amyotrophic lateral sclerosis)

  
  
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  Central sleep apnea due to opioid or other drug abuse

  
  
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  Central sleep apnea due to high altitude periodic breathing

  
  
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  Treatment-emergent central sleep apnea (TECSA)

Adult CSA can be further divided into 2 main categories based on the PaCO2 levels on awakening. ^{, ,} The first type is hypocapnic/eucapnic CSA which is characterized by primary (idiopathic) CSA, heart failure-induced CSA, CSA induced by renal failure or other comorbidities, high altitude-induced CSA, and treatment-emergent CSA. The second type is hypercapnic CSA characterized by medication/drug induced CSA and CSA due to neuromuscular disorders. The distinction between hypercapnic vs. eucapnic/hypocapnic (nonhypercapnic) CSA is useful in the identification of the underlying disease/context and deciding on the appropriate ventilator treatment.

Patients with a reduced cardiac output, decreased left ventricular systolic function, and/or atrial fibrillation frequently develop CSA with Cheyne-Stokes breathing. In these patients the low cardiac output delays the signal of the increased blood carbon dioxide concentration during apnea/hypopnea to the ponto-medullary respiratory centers in the brain and significantly limits the brain’s ability to maintain a steady rate of breathing. Breathing then becomes rapid to reduce the carbon dioxide concentration in the blood. However the breathing pattern overcorrects the carbon dioxide concentration and causes an abnormally low concentration of carbon dioxide in the blood. In response, breathing then stops or slows, overcorrecting and restarting the cycle of hyperventilation followed by apnea/hypopnea. Fig. 4 shows the polysomonographic record of an individual with Cheyne Stokes respiration.

Polysomnography of a patient with Cheyne Stokes respirations.

Fig. 4 shows the crescendo-decrescendo pattern of airflow and respiratory muscle effort during Cheyne Stokes respiration. The length of the Cheyne-Stokes ventilatory cycle is directly proportional to the lung-to-brainstem chemoreceptor circulation time and inversely proportional to the cardiac output. ^, Cheyne-Stokes breathing in patients with CSA may also be observed during the day and the arterial PaCO2 in these patients during awake hours is usually less than 40 mmHG.

Male gender, older age, sedentary lifestyle, the presence of atrial fibrillation, ischemic and dilated cardiomyopathy predispose to Cheyne-Stokes respiration. Cheyne Stokes breathing may also occur in 6 to as many as 72% of the patients with cerebral vascular events (strokes) and is more common in hemorrhagic strokes than ischemic infarctions. When Cheyne Stokes respiration does occur in patients with heart failure or stroke, the prognosis is poor.

Central sleep apnea also can occur with drug abuse such as opioid abuse which depresses the central ventilatory drive and results in hypoventilation, hypoxemia and hypercarbia with ataxic or erratic breathing. ^, Benzodiazepines and baclofen also depress the central ventilatory drive, blunt the response to hypoxia and hypercapnia, leading to CSAs, and increase the risk for OSA by increasing upper airway obstruction through reductions in genioglossus and geniohyoid muscle tone. In addition, the P2Y12 receptor antagonist ticagrelor can result in reductions in ventilatory drive in the respiratory centers and CSA.

Central sleep apnea can be associated with obstructive sleep apnea and can occur in a patient with OSA after restoring the upper airway patency with treatments including positive pressure therapy, an oral appliance, hypoglossal nerve stimulation therapy, or tracheostomy. This form of CSA occurs in approximately five percent of patients and is referred to as Treatment-Emergent Central Sleep Apnea (TECSA) or complex sleep apnea. TECSA represents unmasking of the underlying breathing instability in patients with OSA. ^, Risk factors for TECSA include male sex, older age group, decreased body mass index, higher baseline AHI and arousal index, chronic medical issues such as chronic heart failure and coronary artery disease and opioid use. The identification of these risk factors and the diagnosis of TECSA is important, as patients with TECSA are at high risk of developing CPAP intolerance and discontinuing therapy.

Diagnostic modalities in sleep apnea

Patient questionnaires have been developed to screen for sleep apnea, including the STOP-Bang questionnaire, the Berlin Questionnaire and the Epworth Sleepiness Scale. , the NoSAS score. and the NoApnea score. These screening questionnaires focus on patient symptoms, anthropometric characteristics associated with obstructive sleep apnea, and have been developed and validated in the general population. However, these screening tools have moderate sensitivity and low to moderate specificity for OSA whereas polysomnography has the highest sensitivity and specificity for diagnosis sleep apnea.

Table 1 lists the currently available devices that are available for the evaluation of sleep disordered breathing and the advantages and disadvantages of the devices. Table 1 is adapted in part from References. ^,

Pathophysiologic mechanisms in obstructive and central sleep apnea

Apneas and hypopneas are associated with four acute adverse consequences: 1) Intermittent hypoxemia and hypercarbia; 2) Increased systemic norepinephrine and epinephrine concentrations; 3) large intrathoracic pressure swings; and 4) frequent arousals from sleep. These consequences are qualitatively similar for OSA and CSA, but are more pronounced in OSA.

Chronic intermittent hypoxia and repeated night time arousals cause increased norepinephrine and epinephrine release from sympathetic nerve endings and the adrenal gland, decrease parasympathetic nerve activity, activation of the renin-angiotensin-aldosterone system, and endothelin release. This results in surges in systemic blood pressure, systemic hypertension, increased heart rate, and vascular endothelial dysfunction.

Large intrathoracic pressure swings increase the transmural pressures of the atria, ventricles, intrathoracic aorta, and increase LV afterload, decrease stroke volume and significantly increase myocardial oxygen requirements. ^, In healthy individuals, intrathoracic pressure during inspiration is approximately -8 cm H2O (-5.8 mmHg). In patients with OSA, attempts to breath against an obstructed upper airway generates negative intrathoracic pressures of approximately -30 cm H2O (-22.1 mmHg). These large pressure shifts during OSA increase venous return to the right heart and increase LV afterload, increase cardiac wall stress, and decrease LV compliance which contribute to ventricular remodeling. Approximately 20 to 30% of patients with chronic OSA also have pulmonary hypertension and increased RV afterload. The thin-walled left and right atria are vulnerable to the surrounding negative pressure and stretch easily, which facilitates the development of atrial dysrhythmias.

Intermittent hypoxia promotes significant oxidative stress and systemic inflammation due to activation of nuclear factor kappa B, inflammatory cytokines (interleukin-6, tumor necrosis factor-alpha), chemokines (monocyte chemoattractant protein-1, interleukin-8), cell adhesion molecules (intercellular adhesion molecule-1), and enzymes (cycloxygenase-2) ^, In this regard, the serum concentrations of C Reactive Protein (CRP) and TNFa correlate with the AHI, the oxygen desaturation index (ODI), and the percent time the arterial oxygen saturation is less than 90% and inversely correlate with the lowest oxygen saturation in individuals with sleep apnea. ^, In addition, the concentration of the intercellular adhesion molecule-1 positively correlates with the oxygen desaturation index.

Intermittent hypoxia increases the generation of sterol regulatory element binding protein-1 and stearoyl coenzyme A desaturase-1, the peroxidation of lipids, HDL dysfunction, and increases the total cholesterol concentration in the serum which contributes to the development of dyslipidemia, the formation of vascular atherosclerotic plaques and subsequent coronary artery obstructive disease. ^, Increased oxidative stress also suppresses nitric oxide formation, which results in vascular endothelial cell dysfunction, dysregulation of vascular vasomotor tone, and vascular atherosclerosis. In the microcirculation, the production of the reactive nitrogen species peroxynitrite is significantly increased during hypoxia which also contributes to microvascular dysfunction.

Chronic cycles of hypoxia then deoxygenation also activate the phospholipase C pathway which leads to synthesis of lef-1. This results in decreases in mitochondrial and myocyte function, increases in endothelin-1 and vasoconstriction, and ultimately can contribute to myocardial ischemia and infarction. In addition, recurrent hypoxia activates platelets and increases platelet aggregation which contributes to vascular thrombosis and myocardial ischemia/infarction. In this regard, the degree of platelet activation positively correlates with the severity of oxygen desaturation during sleep. ^,

Fig. 5 summarizes the different pathophysiologic mechanisms that contribute to cardiovascular disease in patients with sleep apnea. Fig. 5 is adapted in part from Reference.

Sleep apnea: pathophysiologic mechanisms.

Epidemiological data suggest that sleep apnea, especially OSA where the majority of investigations have been performed, can contribute to the development of cardiovascular disease (CVD) and amplify the severity of CVD. Repeated nightly episodes of intermittent hypoxia, sympathetic nervous system activation and abrupt swings in intrathoracic pressure can cause blood pressure surges, sustained hypertension, cardiac ischemia and contribute over time to cardiac structural and electrical remodeling, decreased left ventricular systolic and diastolic function, heart failure, cardiac dysrhythmias, stroke and sudden cardiac death. Obstructive sleep apnea can contribute to CVD not only in older adults but also in adults 20 to 40 years of age.

Sleep apnea and cardiovascular disease: Hypertension, Acute Myocardial Infarction, Congestive Heart Failure, Cerebral Vascular Disease (Stroke), and Cardiac Dysrhythmias

Treatment of sleep apnea: a multidisciplinary approach

Alternative treatments for OSA

Hypoglossal nerve stimulation is available for patients with moderate to severe obstructive sleep apnea who do not tolerate CPAP because of discomfort, air leaks, failure to improve, nasal blockage, and/or claustrophobia. A generator/sensor device with two leads (Inspire UAS System) is surgically implanted under the clavicle. A stimulation lead is attached to a distal branch of the hypoglossal nerve which controls the genioglossus muscle in the tongue. The second lead is attached to the fourth or fifth intercostal muscle in order to detect the respiratory cycle. The device is designed to sense ventilatory effort and provide stimulation to the hypoglossal nerve in synchrony with respiration. Hypoglossal nerve stimulation increases muscle tone to selected upper airway muscles innervated by the hypoglossal nerve and causes the tongue to move forward in the mouth thereby preventing upper airway obstruction during sleep. In the Stimulation Therapy for Apnea Reduction (STAR) study, 98 patients with OSA treated with hypoglossal nerve stimulation were followed for 36 months. The self-reported daily device usage was 81%. Patient polysomnography was performed at 12, 18 and 36 months. In 73 patients the AHI was reduced from the median value of 32.0 ± 11.8 events per hour at baseline to 11.5 ± 13.9 events/hour at 36 months. Soft or no snoring reported by the bed partner increased from 17% at baseline to 80% at 36 months. Ninety-one of the 98 patients were followed for a total observation time of 48 months. In response to hypoglossal nerve stimulation during sleep, daytime sleepiness as measured by Epworth Sleepiness Scale (ESS) was significantly reduced (7.3 ± 4.9 versus baseline 11.4 ± 5.1) and sleep-related quality of life as measured by Functional Outcomes of Sleep Questionnaire (FOSQ) significantly improved (17.5 ± 2.9 versus 14.6 ± 3) when compared with baseline. Soft to no snoring was reported by 85% of the bed partners. Two patients required additional surgery for lead malfunction. Seventy-five patients reported nightly use of the device at 48 months. The authors of this study conclude that hypoglossal nerve stimulation can produce a sustained benefit on patient-reported outcomes (ESS, FOSQ, snoring) at 48 months and is an effective treatment for patients with moderate to severe obstructive sleep apnea.

The optimization of hypoglossal nerve stimulation requires careful patient selection, electrode configuration and placement, and evaluation of tongue activation patterns. Current contraindications for the use of hypoglossal nerve stimulation include patients with central and/or complex apneas >25% of the total apnea-hypopnea index (AHI), anatomical abnormalities that compromise the performance of upper airway stimulation, such as the presence of complete concentric collapse of the soft palate, a BMI>40 kg/m ² , severe cardiopulmonary disorders, and active psychiatric disease that confound functional sleep-related assessments. ^,

Other surgical treatments may include uvulopalatopharyngoplasty which can be considered in selected patients with severe OSA who do not respond to or do not tolerate CPAP treatment. However, uvulopalatopharyngoplasty or laser-assisted uvuloplasty are not uniformly successful in decreasing the AHI or improving patient outcomes, and are not currently routinely recommended. Maxillomandibular advancement can also be an option for highly selected patients with OSA with a decreased mandibular or maxillary length who are intolerant of other therapies. However, this procedure can be associated with bone segment displacement, non-union of the maxilla or mandible, facial nerve injury, complete anesthesia of the lip or chin, severe malocclusion, bleeding or infection.

Oral appliances are recommended as the initial treatment for patients with mild to moderate OSA. The oral devices are either mandibular advancement or tongue-retaining devices. After the oral appliance has been custom fitted, a polysomnographic test or home sleep study should be obtained to evaluate treatment efficacy. In general, oral appliances modestly improve daytime sleepiness and blood pressure but decrease the AHI to a lesser extent than CPAP treatment. ^, Adverse effects of oral appliances include aggravation of temporomandibular joint dysfunction, jaw pain, teeth shift, gingival irritation, excessive salivation or dry mouth. Consequently, regular dental evaluations are important for all patients with OSA who are prescribed oral appliances.

Additional treatment options for patients with OSA include myofunctional therapy exercises to strengthen oropharyngeal muscles, tonsillectomy and adenoidectomy in young patients when tonsillar enlargement encroaches on the upper airway, and tracheostomy, which is highly effective but rarely utilized currently unless other treatments are ineffective and there is substantial patient comorbidity.

Treatment of central sleep apnea

In patients with CSA, clinicians should focus on the optimization of treatment for comorbid conditions, especially if concurrent OSA is present. If that does not resolve CSA, CPAP can be beneficial in decreasing the AHI, especially in patients with CSA and Cheyne Stokes respiration. In an investigation of 29 patients with CSA with Cheyne-Stokes respirations and heart failure, CPAP produced an 8% increase in LVEF at 3 months and a relative risk reduction of 81% in patient mortality or cardiac transplantation rate over 2.2 years. In the patients in this study, the dedicated use of CPAP was required for approximately 6 h/night for three months in order to be beneficial. However in this study, CPAP had no significant effect on either mortality or cardiac transplantation in patients with CSA without Cheyne Stokes respiration.

The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure trial (CANPAP trial) tested the hypothesis that CPAP would improve the survival rate without heart transplantation of patients who have central sleep apnea and heart failure. In this study, CPAP treatment compared with no CPAP treatment significantly decreased the frequency of apnea or hyponea by 21/h vs. –2/h, increased nocturnal oxygenation by 2% vs. 0.4%, increased the LV ejection fraction by 2% vs. 0.4%, decreased norepinephrine concentrations by 1. vs. 0.02 nmol/L, and increased the distance walked in six minutes to 20. vs. –0.8 m. The trial demonstrated that CPAP can attenuate central sleep apnea, improve nocturnal oxygenation and left ventricular systolic function, and lower plasma norepinephrine concentrations, and showed that these effects can be sustained over a mean of two years. However in this study, CPAP did not increase patient survival. In a post-hoc analysis of the CANPAP trial, an increase in the LV ejection fraction and transplant-free survival occurred in 57% patients in whom AHI was reduced to <15/h. No benefits were observed in 43% of patients in whom CPAP did not reduce the AHI to <15/h.

In patients with CSA with Cheyne-Stokes respirations that are poorly responsive or unresponsive to CPAP treatment, bilevel positive airway pressure (BPAP), which cycles between two levels of continuous positive airway pressures, is an alternative treatment option but should not be used with a back-up breathing rate. ^,

Experience with adaptive servo ventilation (ASV) in the treatment of patients with CSA and heart failure has been disappointing based on the results of three large trials. The multicenter Adaptive Servo Ventilation for Central Sleep Apnea in Systolic Heart Failure (SERVE-HF) trial involving 1325 participants showed that ASV decreased the AHI but increased the risk of cardiovascular mortality, possibly due to a decrease in the cardiac output from positive airway pressure. Results from the Cardiovascular Improvements with minute ventilation targeted adaptive servo ventilation Therapy in Heart Failure (CAT-HF) Trial involving 125 participants also demonstrated a reduction in the AHI but no improvement in 6-month cardiovascular outcomes in patients receiving ASV plus current optimal medical therapy compared with current optimal medical therapy alone. Similarly in the Effect of ASV on Survival and Hospital Admissions in HF (ADVENT-HF) Trial, ASV and standard of care therapy in 375 patients with SDB over 3.6 years had no significant effect on the composite endpoint of all-cause mortality, first admission to hospital for a cardiovascular problem, new onset atrial fibrillation or flutter, or delivery of an appropriate cardioverter-defibrillator shock and no significant effect on a secondary endpoint of all cause mortality compared with standard of care alone. Nevertheless in the ASV group, the mean AHI decreased to 3–4 events per hour over the course of the trial and was associated with improvements in sleep quality.

CSA can be eliminated by cardiac transplantation, which suggests that severe heart failure may be causative of CSA. However within several months following cardiac transplantation, more than one-third of patients develop OSA due to weight gain, lack of physical exercise, decreased quality of life, and possibly heart rejection.

Medications

Patients with persistent daytime sleepiness may benefit from medications such as modafinil, to promote wakefulness. Modafinil binds to the dopamine transporter and inhibits dopamine reuptake and removal in the brain. However, modafinil must be used with caution in patients with cardiac disease because of possible hypertension, tachycardia, extrasystoles, and drug interactions with propranolol/metoprolol. Beta-adrenergic antagonists, such as carvedilol, can decrease the nocturnal cardiac sympathetic hyperactivation that occurs in patients with SDB due to repetitive nocturnal arousals and hypoxemia. Angiotensin receptor-neprilysin inhibitors and loop diuretics, such as furosemide or torsemide, can decrease nocturnal water shifts and cause lung and neck decongestion, decrease the plasma volume, and increase the circulation time, which can be beneficial in CSA and OSA. Acetazolamide, which causes mild metabolic acidosis and results in increased respiratory drive, can decrease the frequency of central apneas and the AHI and can increase oxygen saturation in patients with CSA. In this manner, acetazolamide can improve functional capacity and sleep quality. Theophylline, which can inhibit adenosine receptors in medulla and increase ventilatory stimulation, can be used in the treatment of CSA in patients with heart failure. However the central nervous system stimulating actions of theophylline can disrupt sleep time and efficiency and limit the use of this drug in CSA treatment. Other potential adverse effects from theophylline include cardiac arrhythmias and gastrointestinal irritation. Since theophylline has a narrow therapeutic index, close monitoring of theophylline serum concentrations is necessary.

Compliance with ethical standards

The authors have no potential conflicts of interest. This is a Review Article. No human studies or animal studies were carried out by the authors for this article.

Ethical approval

This article does not contain any studies with humans or with animals performed by the authors.

Financial & competing interests disclosure

Work in the cardiovascular research laboratory of RJH is supported by a grant from the Cardiomyopathy Foundation. The author has no other relevant affiliations and no financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. No writing assistance was utilized in the production of this manuscript