Clinical manifestations

Presentation and course

Patients with cardiovascular diseases may complain of several sleep disturbances, such as sleep fragmentation, insomnia, and breathing disorders, during sleep. However, patients with sleep disorders seem to be more frequently affected by cardiovascular disorders. Sympathetic activation and subsequent endothelial dysfunction play a role in both sleep disordered breathing and cardiovascular disease. Hence, this may be the underlying mechanism for the bidirectional relationship (120). Several prospective studies have shown that sleeping less than 7 hours or more than 9 hours increases the risk of hypertension, metabolic syndrome, myocardial infarction, and other cardiovascular diseases (78). Some conditions that can affect sleep duration, such as insomnia, can also play a role in the development of cardiovascular disease. Indeed, data obtained through Mendelian randomization showed that genetically predicted insomnia was causally associated with increased risk of all cardiometabolic diseases evaluated (ischemic stroke, coronary artery disease, heart failure, and type 2 diabetes) (50).

The symptoms of heart failure are well known, including fatigue, dyspnea with exercise, or if severe, at rest. On physical examination, the patient may have pitting edema in the legs, hepatic enlargement, neck vein distension, and rales by auscultation. If the heart failure is due to valvular disease, there will be murmurs. If it is due to hypertension, the blood pressure will be elevated.

Patients with heart failure often complain of sleep disruption potentially related to sleep-related breathing disorders. Two forms of sleep apnea are of major interest in heart failure: obstructive sleep apnea (OSA) and central sleep apnea. Obstructive apnea is secondary to complete collapse of a narrowed pharynx, whereas central apneas arise from reductions in central respiratory drive. During obstructive apnea, the effort of abdominal and thoracic muscles is increased to improve airflow viability. In contrast, respiratory movements are absent in central apnea.

Oscillatory breathing alternating between hyperpnea and central apnea during sleep was recognized more than a century ago in cardiac patients (Cheyne-Stokes respiration). Central sleep apnea or Cheyne-Stokes respiration is approximately four to five times more common than OSA in patients with heart failure and, when combined, they affect 40% to 60% of patients. Male sex and obesity are the chief risk factors of OSA. In addition, periodic oscillation in ventilatory drive related to Cheyne-Stokes respiration may cause withdrawal of pharyngeal dilator muscle tone, predisposing to upper airway narrowing or collapse in patients with heart failure.

One of the proposed mechanisms to explain the association between sleep-related breathing disorders and heart failure is the theory of “fluid shift.” During the day, fluid is accumulated by gravity in the feet and legs of the patient; when recumbent for sleep, the edema is reabsorbed into the circulating blood volume and increases the edema in the lungs, but also in the upper airways, increasing the possibility of their collapse. Intermittent hypoxia is the primary cause of obstructive sleep apnea-related cardiovascular comorbidities. Its vicious cycle of hypoxia-reoxygenation leads to the formation of reactive oxygen species that further cause endothelial dysfunction (85). Detrimental effects of sleep-disordered breathing include hemodynamic abnormalities, neurohormonal activation, inflammation, and endothelial dysfunction, ultimately leading to increased heart failure risk and worse prognosis in patients with overt heart failure.

Paroxysmal nocturnal dyspnea and nocturia are frequently observed in heart failure patients, and they can represent additional causes of sleep disruption significantly affecting sleep quality and duration in heart failure patients. Also, arrhythmias (atrial fibrillation, nocturnal asystole, nonsustained ventricular tachycardia) can be associated with sleep disturbances, particularly with obstructive sleep apneas.

Prognosis and complications

Cardiovascular complications of obstructive sleep apnea. There is increasing evidence that untreated severe obstructive sleep apnea can lead to serious or fatal complications (79). The main randomized controlled trials aimed at evaluating the effect of OSA treatment on the improvement of cardiovascular risk failed in demonstrating any significant benefit in treating OSA for cardiovascular prevention (82; 94; 104). However, some differences should be mentioned according to the relationship between OSA and the different cardiovascular complications.

Stroke. Compared to normal controls, patients with stroke have an increased incidence of OSA. A higher percentage of silent ischemic brain lesions has been described in patients with moderate to severe OSA (25.0%) compared to obese control subjects (6.7%) or patients with mild OSA (7.7%). Little is known about the clinical relevance of OSA in the acute phase (first few days) of ischemic stroke, and the limited information available suggests an association between OSA severity and stroke severity. Considering the evolution in the weeks/months following stroke, sleep-related breathing disorder was shown to be associated with duration of hospitalization, increased mortality, and poor functional outcome (70).

One paper showed that sleep-disordered breathing was associated with significantly increased levels of inflammatory biomarkers, providing possible pathophysiological explanation of OSA-associated stroke risk (60). But again, when evaluating the association between OSA and stroke in interventional randomized trials, the treatment of the former is not associated with a reduction in cerebrovascular events (48). Nevertheless, it appears that CPAP treatment confers protection in the development of stroke only in patients with adequate adherence to treatment.

Ischemic heart disease. The risk for ischemic heart disease is almost twice as high for habitual snorers as it is for nonsnorers and remains elevated after controlling for the effects of age, hypertension, smoking, obesity, and alcohol use. A published meta-analysis concluded that the relationship between OSA and ischemic heart disease needs more evidence (70), but a systematic review analyzing studies on noninvasive evaluation of subclinical cardiovascular diseases (CVD) showed that OSA is an independent predictor of subclinical CVD and that CVD is more likely to occur in patients with long-standing and severe OSA (01).

Cardiac arrhythmias. Cardiac arrhythmias are serious complications of OSA. A pattern of repeated cycles of bradycardia during the apnea, followed by tachycardia with arousal that terminates the apnea, is the most common. Other arrhythmias include sinus arrest lasting up to 10 seconds, second- or third-degree heart block, premature ventricular contractions, and potentially lethal tachyarrhythmias. The mechanism for bradycardia appears to be a reflex increase in cardiac vagal tone caused by stimulation of carotid body receptors by hypoxemia. Increased vagal tone also contributes to periods of asystole and arterioventricular block. The progressive increase in sympathetic tone during an apneic event, reaching its maximum during the arousals at the end of apneas, appears to contribute to premature ventricular contractions, sinus tachycardia, and ventricular tachyarrhythmias. Hypoxemia also increases ventricular irritability. Arrhythmias are more common during REM sleep, probably because of more severe hypoxemia and because of autonomic discharge related to phasic events of REM sleep. It is also suggested that OSA represents an important, independent risk factor for the appearance and recurrence of atrial fibrillation, particularly in patients with hypertrophic cardiomyopathy (05; 30; 102; 122; 03; 88).

Observational studies suggest that sleep-disordered breathing treatment reduces atrial fibrillation recurrence after rhythm control interventions. However, high-level evidence from clinical trials that supports a role for sleep-disordered breathing intervention on rhythm control is currently not available.

Congestive heart failure. Much attention has been focused on the effects of sleep-disordered breathing (central and obstructive sleep apnea syndrome) in determining cardiac failure, and vice versa. The role of cardiac dysfunctions can also be considered a possible determinant of sleep-disordered breathing, but there are studies suggesting a role of sleep-related breathing disorders, particularly changes in intrathoracic pressure associated with hypoxia, in determining alterations in left and right ventricular mechanics.

Male gender and obesity are the chief risk factors of OSA, as in the general population. In addition, periodic oscillations in ventilatory drive related to Cheyne-Stokes respiration may cause withdrawal of pharyngeal dilator muscle tone, predisposing to upper airway narrowing or collapse in heart failure patients. Shift of fluids from the legs to the thorax in the recumbent position during sleep favors fluid accumulation in the upper airway, pharynx narrowing, and collapse. Unlike OSA, central sleep apnea seems more directly related to heart failure. Hypocapnia secondary to hyperventilation is the main mechanism of central apnea in patients with congestive heart failure. Detrimental effects of sleep-disordered breathing include hemodynamic abnormalities, neurohormonal activation, inflammation, and endothelial dysfunction.

The presence of sleep-disordered breathing in heart failure patients may be associated with adverse prognosis, probably due to worsening of ventricular function and heart failure symptoms. OSA may reduce systolic cardiac function by increasing afterload due to negative intrathoracic pressure generated during respiratory efforts against an occluded upper airway and is frequently associated with hypertension and vascular disease. Both OSA and central sleep apnea may also be associated with a higher incidence of atrial and ventricular arrhythmias in heart failure patients. In some studies, sleep-disordered breathing induces cardiac electrical instability, increasing the risk of sudden cardiac death.

Technological progress has allowed for variations in the mode of delivering positive pressure ventilation. One such method is adaptive servo-ventilation (ASV), which provides a small but varying amount of ventilatory support against a background of low level CPAP. There is evidence that ASV is more effective than CPAP for the treatment of sleep apnea (110; 55; 117). Unfortunately, the results of the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Auto Servo Ventilation in Patients with Heart Failure (SERVE-HF) trial showed that adaptive servo-ventilation (ASV) treatment in patients with a left ventricular ejection fraction of 45% or less and predominantly affected by central sleep apnea resulted in an increased rather than in a reduced cardiovascular mortality (26). However, caution is needed in extending the results of the SERVE-HF trial outside these study conditions, as mentioned before (72).

The results of another randomized controlled trial (Effect of Adaptive Servo Ventilation on Survival and Hospital Admissions in Patients with Heart Failure and Sleep-disordered Breathing - ADVENT-HF, # NCT01128816) will be available soon. In the meantime, treatment with peak flow–triggered ASV in patients with HFrEF and coexisting obstructive or central sleep apnea with the aim of improving survival and frequency of hospital admissions are not recommended.

Hypertension. Habitual snoring also appears to be an independent risk factor for the development of hypertension, and even low levels of sleep-disordered breathing appear to increase the risk for hypertension. Among various sleep breathing disorders, obstructive sleep apnea has been increasingly associated with treatment resistant hypertension and reduced physiological nocturnal blood pressure dipping (29). In beat-by-beat recordings of blood pressure, OSA patients show continuous oscillations associated with apneas. A positive evening-to-morning change in blood pressure and increased mean blood pressure during sleep has been reported in patients with OSA. In addition, the nocturnal blood pressure pattern observed in OSA is profoundly different from the physiological fall in blood pressure during sleep and contributes to increased mean 24-h blood pressure values in OSA patients. The non-dipper condition appears to be associated with OSA. Increased blood pressure in untreated OSA patients may be limited to nocturnal hours, but also occurs during wakefulness, possibly as a consequence of changes in autonomic cardiovascular control involving the activity of arterial baroreflexes and peripheral chemoreceptors. Several studies reported a positive correlation between mean blood pressure over 24 hours and OSA severity. For these reasons, it is important for hypertension management protocols to include investigation of coexisting sleep disorders in patients with treatment resistant hypertension.

Among the different mechanisms involved in the pathogenesis of nocturnal hypertensive peaks, OSA-associated intermittent hypoxia probably plays a major role. Recordings of sympathetic nervous activity during sleep have shown increased burst frequency and duration during OSA, abruptly abolished at resumption of ventilation. Hypertensive peaks coincide with the lowest values of oxygen saturation and are associated with peripheral vasoconstriction. However, respiratory efforts during upper airway obstruction are associated with increased blood pressure during sleep in clinical and experimental studies. Breathing efforts exert complex effects on hemodynamics by causing large changes in transmural pressure of intrathoracic vessels and the heart. During obstructive apneas in humans, left ventricular stroke volume correlates inversely with intrathoracic pressure.

Although mean blood pressure values in OSA patients may be similar to those recorded in controls, OSA patients show a much higher blood pressure variability than controls. Increased blood pressure variability has been found to independently predict cardiovascular events, although the relative importance of increased mean blood pressure levels and increased blood pressure variability is still under debate.

Moreover, an interesting paper showed that in patients not considered to have OSA, because their total AHI was less than 10, hypertension was related to OSA appearing selectively during REM sleep (04).

Sleep disruption is another potential pathogenetic factor in OSA-associated nocturnal and daytime hypertension. Arousals during sleep acutely increase blood pressure in normal subjects, non-apneic snorers, patients with upper airway resistance syndrome, and patients with OSA. Evidence by Pinilla and coauthors confirms that respiratory arousal index was a key OSA-related parameter associated with the loss of nocturnal blood pressure dipping (99).

Prevalence of daytime hypertension in OSAS patients ranges from 35% to 80% and appears to be influenced by OSA severity. Over 60% of subjects with a respiratory disturbance index of 30 were found to be hypertensive. As for the type of daytime hypertension associated with OSA, the majority of patients showed systolic and diastolic hypertension or isolated diastolic hypertension.

OSAS is a recognized cause of resistant (or refractory) hypertension, which is defined as the absence of normalization of blood pressure despite antihypertensive treatment with three or more drugs, including a thiazide diuretic. In these patients, OSA treatment improved blood pressure control, in case of effective and regular CPAP application, suggesting a major causal role of OSA in the pathogenesis of resistant hypertension (80; 35). The pathophysiology of hypertension in OSA patients probably includes the activation of multiple mechanisms, which may exert synergistic detrimental effects on blood pressure regulation.

Increased sympathetic activity in OSA patients is not limited to the sleep state but extends to wakefulness, possibly as a result of the disrupting effects of chronic intermittent hypoxia on the function of the carotid body. Increased pressor responsiveness to peripheral chemoreceptor stimulation has been found in awake OSA patients, together with increased cardiovascular variability and decreased baroreflex function. Endothelial dysfunction could play a major role in the pathogenesis of daytime hypertension in OSA. Several reviews have summarized the extensive literature on this topic in adults and children. The endothelium normally contributes to vascular homeostasis, but the hypoxia-oxygenation cycles occurring in OSA disrupt endothelial cell function. Oxidative stress occurs in OSA and could participate in several proinflammatory pathways in circulating inflammatory and endothelial cells. Clinically, endothelial function was found to be impaired in untreated OSA and associated with decreased bioavailability of nitric oxide, a potent vasodilator. There is also strong evidence that metalloproteinase levels are elevated in patients with OSA. A systematic review demonstrated elevated MMP-9 levels in OSA, systemic hypertension, myocardial infarction, and heart failure (81).

Some studies assessed whether OSA may induce a procoagulant state. Increased platelet aggregability was found in patients with severe OSA during sleep and wakefulness, returning towards normal values after prolonged CPAP treatment.

Evidence has confirmed that intermittent hypoxia promotes the complement-mediated release of von Willebrand factor and angiopoietin-2, which may contribute to prothrombotic and proinflammatory conditions in OSA. Interestingly, in the same study authors showed that statin reversed these effects, suggesting a potential approach to reduce cardiovascular risk in OSA (40).

Hormonal dysregulation can affect blood pressure in OSA patients. Increased angiotensin-II and aldosterone were found in untreated OSA, together with a positive correlation between angiotensin-II concentration and daytime blood pressure. Although a significant association of OSA and increased aldosterone has been shown in patients with resistant hypertension, a normal aldosterone concentration has been found in moderate-to-severe OSA patients without cardiovascular comorbidities compared to controls. Other hormones are affected by OSA and may contribute to the pathogenesis of hypertension, including the hypothalamic-pituitary-adrenal axis (HPA) and cortisol (92; 93).

Clinical vignette

A 55-year-old male had been in general good health but was overweight, hypertensive, and had smoked cigarettes for 30 years. His cholesterol was elevated with an increase in the low-density lipids. For the last 5 years, he had experienced chest pain when exerting. He began to be awakened from sleep with a similar pain, but it was not frequent enough to disturb his overall sleep. His physical examination revealed no remarkable findings but a blood pressure of 190/100 mm Hg. He was started on antihypertensive medications and gave up cigarettes but had sudden onset of persistent chest pain that radiated into his left arm. He was admitted to the hospital where an extensive anterior myocardial infarction was found. After stabilization, percutaneous angioplasty was performed, but his left ventricle had a large area of dyskinesis representing the area of infarction, and his ejection fraction was poor. After discharge, it became evident that he had dyspnea on even slight exertion. He reported that he did not sleep well and frequently dozed off during the day. On clinical examination, he had a few rales at the base of his lungs, and on chest x-ray an enlarged heart plus pulmonary venous congestion was seen. His wife reported that he had frightening episodes of respiratory cessation at night, whereupon a sleep study revealed that he had Cheyne-Stokes respirations.

He began digitalis, diuretics, an angiotensin-converting-enzyme inhibitor, and a trial of CPAP with supplemental oxygen that improved his sleep. He still had difficulty working and was referred for consideration of a heart transplant.

Biological basis

Etiology and pathogenesis

The disease-causing periodic breathing in the clinical vignette was heart failure due to ischemic cardiomyopathy secondary to severe coronary artery disease related to untreated hypertension. Sleep fragmentation was secondary to Cheyne-Stokes respiration resulting from heart failure that produced an enlarged heart, a long circulation time from the lung to the carotid chemoreceptor, and diminished vital capacity due to pulmonary edema leading to chemoreceptor stimulation and then to periodic breathing.

Sleep-related breathing disorders, particularly obstructive sleep apnea, could play a role in determining cardiovascular risk, including ischemic cardiac disorders. Ischemic cardiomyopathy, together with arterial hypertension, is, in fact, one of the most frequent causes of heart disease associated with obstructive sleep disorders and may begin with an acute “coronary syndrome” (32). Other cardiac causes of sleep disorders are dilated and hypertrophic cardiomyopathies, severe valvular disorders, and congenital heart diseases.

There is a close relationship between the cardiovascular and respiratory systems and between these systems and sleep, leading, in turn, to the peculiar cardiovascular and respiratory changes during the sleep-wake cycle (67). The physiological (respiratory and cardiovascular) changes during sleep may be disrupted in several pathological conditions, where cardiovascular and sleep alterations can be variably associated.

Quality and duration of sleep. Quality and duration of nocturnal sleep have been reported as factors affecting health status in a population, particularly the cardiovascular risk profile. In particular, sleep features and sleep disorders seem to play an important role in determining blood pressure levels, both in the office and over 24 hours, and in modulating the day-night blood pressure profile, which can have an impact on the prognosis of hypertensive patients. Evidence indicates that both increased and reduced sleep duration (ie, a sleeping period equal to or shorter than 6 hours and equal to or longer than 9 hours, respectively) may be associated with an increased risk of cardiovascular disease (16; 28; 24; 111). The Sleep Heart Health Study showed that usual sleep duration, both above or below the median range of 7 to 8 hours per night, is associated with an increased prevalence of hypertension, an association that became particularly frequent when sleep time was less than 6 hours per night (43).

Various studies have indicated that duration of sleep is indeed related to poor eating habits and short or long sleepers tend to consume more food, which further causes cardio-metabolic abnormalities like diabetes, obesity, and OSA, hence, increasing cardiovascular risks. A multivariable logistic regression analysis was performed on data collected from 32,152 participants from the U.S. general population between 2005 and 2016 (59). It showed that short sleep duration (less than 7 hours) was associated with a higher prevalence of previous stroke (OR 1.45), heart failure (OR- 1.65), diabetes mellitus (OR-1.35), and hyperlipidemia (OR-1.12). Long sleep duration was also associated with high prevalence of previous stroke (OR-1.81) and heart failure (OR-1.47). All the p values were less than 0.05.

In a randomized controlled trial, Covassin and colleagues showed that experimental sleep restriction in healthy adults combined with ad libitum food promotes excess energy intake without varying energy expenditure (25). Weight gain and particularly central accumulation of fat indicate that sleep loss predisposes to abdominal visceral obesity.

A study in a large cohort of Chinese subjects showed that longer sleep duration and midday napping were independently and jointly associated with a higher risk of coronary heart disease incidence, and altered lipid profile and waist circumference may partially explain the relationships (125).

However, changes in sleep quality may also affect the prevalence of cardiovascular problems, particularly hypertension. Data suggest that subjects with resistant hypertension also have shorter total and REM sleep times and lower sleep efficiency, emphasizing the important role of sleep characteristics per se. However, there are controversial data about the role of insomnia associated with OSA in determining hypertension (45; 74).

The mechanisms by which sleep disturbances, including reduced sleep duration, may lead to an increase in blood pressure levels and to alterations in the 24-hour blood pressure profile are still partly unknown. A link between sleep deprivation/fragmentation and metabolic syndrome has been hypothesized to play a role in this context. In fact, sleep restriction may be associated with an impaired glucose tolerance, dyslipidemia, and increased prevalence of obesity, together with overactivity of the renin-angiotensin-aldosterone system and of the sympathetic cardiovascular drive, blunted autonomic cardiovascular modulation over 24 hours, renal impairment, endothelial dysfunction, and increase in inflammatory indices.

An interesting observation made in a few studies is that sleep deprivation might have a stronger effect on blood pressure levels and cardiovascular and metabolic problems in women than in men (71). In fact, the relationship between self-reported sleep duration and body composition, with a larger degree of fat content, may be stronger in women than in men, with an inverse relationship between sleep duration and BMI or waist circumference being observed only in women.

However, in a Norwegian and Finnish study, insomnia symptoms were associated with mortality among men but not in women (62). The same authors conclude that variation and heterogeneity in the association between insomnia symptoms and mortality highlights that further research needs to distinguish between men and women, specific symptoms, and national contexts, and focus on more chronic insomnia (62).

In addition to gender, age also seems to affect the cardiovascular changes induced by alterations in sleep patterns. Sleep deprivation (quantified as a sleep duration equal to or lower than 5 hours per night) was reported to be associated with a higher risk of hypertension in middle-aged adults, but not in children or elderly individuals (71).

Sleep-related breathing disorders. The most important sleep-related clinical condition affecting cardiovascular control is represented by sleep-related breathing disorders. The failure to maintain a normal breathing pattern during sleep leads to an increase in cardiovascular stress, which is related to an increase in cardiovascular disease.

Obstructive sleep apnea (OSA) is secondary to complete collapse of a narrowed pharynx, whereas central apneas arise from reductions in central respiratory drive. During obstructive apnea, the effort of abdominal and thoracic muscles is increased to improve airflow viability. In contrast, respiratory movements are absent in central apnea. Sleep-related breathing disorders, particularly obstructive sleep apnea syndrome (OSAS), is highly prevalent, at least 4% of middle-aged males and 2% of middle-aged females in the developed world, and this prevalence is growing parallel to the growing prevalence of obesity. Individuals with OSAS have reduced quality of life and excess daytime somnolence and are at increased risk of road traffic accidents when compared with nonapneic subjects. Of more concern from a public health standpoint, however, is the increased risk of cardiovascular morbidity and mortality associated with a diagnosis of OSAS. OSAS is associated with hypertension, myocardial infarction, cardiac arrhythmia, congestive heart failure, and stroke. Indeed, untreated severe OSAS confers a 3-fold increased risk of death from cardiovascular causes (92; 93).

An important prospective study in a population of 10,701 adults showed that OSA predicted incident sudden cardiac death and that the magnitude of risk was predicted by multiple parameters characterizing OSA severity. Nocturnal hypoxemia strongly predicted SCD independently of well-established risk factors (39).

Studies demonstrate an association between impairment of wakefulness and long-term cardiovascular mortality in OSAS patients. These data are supported by a study in which the authors showed that excessive daytime sleepiness in OSA patients is related to impairment of baroreflex sensitivity and of specific indexes of heart rate variability (73).

Cardiac arrhythmias are serious complications of obstructive sleep apnea. A pattern of repeated cycles of bradycardia during the apnea followed by tachycardia with arousal that terminates the apnea is the most common. Other arrhythmias include sinus arrest lasting up to 10 seconds, second- or third-degree heart block, premature ventricular contractions, and potentially lethal tachyarrhythmias. Proposed pathophysiological mechanisms include intermittent hypoxia and hypercapnia, autonomic remodeling, atrial stretch, and inflammation. An analysis of the effect of OSA and obesity on cardiac remodeling in the Wisconsin Sleep Cohort and data show that after adjustment for confounding factors, baseline AHI was associated with future reduced left ventricular ejection fraction and that SaO2 behavior is related to left ventricular mass, left ventricular wall thickness, and right ventricular area (58).

A study exploring the relationship of OSA and atrial fibrillation included 467 patients with OSA both with or without atrial fibrillation. Atrial fibrillation was associated with higher odds of OSA in nonobese patients (OR: 2.29, 95% CI:1.23-4.35, p=0.01), but not in obese patients (OR: 0.95, 95% CI: 0.48-1.90, p=0.89) (113).

Congestive heart failure. Severe nocturnal hypoxemia seen in sleep related breathing disorders is also commonly found in heart failure patients. Oscillatory breathing alternating between hyperpnea and central apnea during sleep in cardiac patients (Cheyne-Stokes respiration) was recognized more than a century ago. Central sleep apnea or Cheyne-Stokes respiration is approximately four to five times more common than OSA in heart failure patients and, when combined, they affect 40% to 60% of subjects. Much attention has been focused on the effects of sleep-disordered breathing (central and obstructive sleep apnea syndrome) in determining cardiac failure, and vice versa. The role of cardiac dysfunction can also be considered a possible determinant of sleep-disordered breathing, but there are studies suggesting the role of sleep-related breathing disorders, particularly changes in intrathoracic pressure associated with hypoxia, in precipitating alterations in left and right ventricular mechanics.

Assessment of right ventricular remodeling and dysfunction in OSA patients showed OSA to be independently associated with structural alterations of the right ventricle (47).

In addition, periodic oscillations in ventilatory drive related to Cheyne-Stokes respiration may cause withdrawal of pharyngeal dilator muscle tone, predisposing to upper airway narrowing or collapse in heart failure patients. Shift of fluids from the legs to the thorax in the recumbent position during sleep favors fluid accumulation in the upper airway, pharynx narrowing, and collapse. Unlike OSA, central sleep apnea seems more directly related to heart failure. Hypocapnia secondary to hyperventilation is the main mechanism of central apnea in patients with congestive heart failure. Detrimental effects of sleep-disordered breathing include hemodynamic abnormalities, neurohormonal activation, inflammation, and endothelial dysfunction (53).

A study done in India showed high prevalence of sleep related breathing disorder in patients with heart failure (81.55%), with OSA being the predominant type (59.2%) (57).

Several studies have shown beneficial effects of continuous positive airway pressure (CPAP) therapy in heart failure patients with either OSA or central sleep apnea. CPAP has been associated with reversal of sleep apnea, improved nocturnal oxygenation, reduced heart rate and daytime systolic blood pressure, reduced sympathetic activation, and better left ventricular function. The Canadian Continuous Positive Airway Pressure (CANPAP) trial failed to prove any beneficial effect of CPAP therapy on transplant-free survival and heart failure–related hospitalizations in spite of significant improvements in nocturnal breathing pattern, left ventricular function, and functional status in heart failure patients with central sleep apnea. However, a post-hoc analysis showed reduced mortality in the subgroup of patients in whom CPAP was effective in reducing central sleep apnea. Moreover, there is increasing evidence on the therapeutic effect of the adaptive servo-ventilation (ASV) device (55; 117).

Adaptive servo-ventilation is a noninvasive ventilatory method, which is well tolerated by the patients and is shown to be more effective than CPAP in treating central sleep apnea. It has been shown to improve BNP levels. Adding adaptive servo-ventilation, however, to the therapeutic regimen of patients with heart failure and Cheyne-Stokes breathing did not improve outcomes and instead increased cardiovascular risk and mortality (103).

Unfortunately, uncertainty on whether central apneas in heart failure patients should or should not be treated has grown even more after the publication of the results of the Treatment of Sleep-Disordered Breathing with Predominant Central Sleep Apnea by Adaptive Servo-Ventilation in Patients with Heart Failure (SERVE-HF) trial.

This study showed that adding adaptive servo-ventilation (ASV) to guideline-based medical treatment in patients with a left ventricular ejection fraction of 45% or less and predominantly affected by central sleep apnea resulted in an increased rather than in a reduced cardiovascular mortality (26).

However, caution is needed in extending the results of the SERVE-HF trial outside these study conditions due to several methodological aspects that may restrict the generalization of this study’s conclusions to all heart failure patients with sleep-related breathing disorder seen in a clinical practice setting (72).

Epidemiology

Sleep-related breathing disorder as a cause of cardiovascular complications. Severe untreated OSA (apnea-hypopnea index [AHI] > 30) has been linked to fatal and nonfatal cardiovascular events, and all-cause mortality.

Ischemic heart disease. Published prospective and cross-sectional reports suggest an association of OSA and coronary artery disease (01). Untreated OSA may adversely influence prognosis in patients with coronary artery disease (64), including percutaneous coronary intervention (65). More controversial is the prognostic role of continuous positive airway pressure in coronary artery disease patients with OSA but nonsleepy (94).

In the Sleep Heart Health study, after adjustment for multiple risk factors, OSA was a barely significant predictor of incident coronary heart disease (myocardial infarction, revascularization procedure, or coronary heart disease death) in men up to 70 years of age (adjusted hazard ratio 1.10 [95% confidence interval 1.00 to 1.21] per 10-unit increase in AHI), but not in older men or in women of any age.

Sleep apnea and stroke. Severe OSA in a Swedish cohort of 182 middle-aged men was associated with a very high cardiovascular risk: over 10 years, 14% of this group was predicted to experience a stroke, and 23% a myocardial infarction (36% combined risk). Prospective data in a larger population confirmed that in a community-based sample of middle-aged and older adults (5422 participants without a history of stroke at the baseline examination and untreated for sleep apnea, who were followed for a median of 8.7 years), incident cardiovascular disease, including stroke, was significantly associated with sleep-disordered breathing in men. A survey of 6424 patients of the Sleep Heart Study showed a relative stroke risk of 1.58 for patients with an AHI of greater than 10/h compared to patients without sleep apnea. Moreover, in another prospective cohort study, patients with an AHI of greater than 10/h had an increased relative combined stroke and death risk of 1.97, rising to 3.3 when AHI was greater than 36/h during a 3-year follow-up period. Finally, evidence-based work has showed that OSA increases the risk of stroke independently of other cerebrovascular risk factors (84). This relationship seems to be more evident in patients with patent foramen ovale (PFO) (52).

Congestive heart failure. Studies show that untreated sleep apnea may promote left ventricular dysfunction, disease progression, and increased mortality in heart failure patients (53; 58). In the Sleep Heart Health Study, the presence of OSA conferred a 2.38 relative risk of having heart failure, independently of other known risk factors. However, because most data were obtained in elderly patients, the role of OSA in increasing the risk of heart failure in relatively young patients is uncertain.

Target organ damage. Strong evidence has been obtained on the crucial role of target organ damage in determining the cardiovascular risk of individuals with high blood pressure. Methods for evaluating organ damage are mentioned in detail in the ESH-ESC 2018 Hypertension Guidelines (123). Data are also available showing that OSA may favor appearance of hypertension-related organ damage (69). One study has highlighted the role of OSA-related nocturnal hypoxia in relation to cardiac organ damage: in a cohort of 162 patients with OSA, a multivariate linear regression analysis showed that hypoxia markers (percentage of time with O2 saturation below 90%) but not the AHI were independent predictors of left ventricular end-diastolic volume and E/A (75). Cardiovascular diseases leading to pacemaker implantations are suspected of being associated with a high rate of undiagnosed OSA. After treatment with CPAP, significant improvements were observed in cardiac symptoms and in hemodynamic parameters, as well as in left and right ventricular morphology and function (92; 93).

Sleep-related breathing disorder as a consequence of cardiovascular diseases. The sleep-related breathing disorder commonly linked to heart failure is central sleep apnea, but the prevalence of OSA in congestive heart failure patients is relatively high (between 10% and 25%), possibly due to upper airway narrowing by fluid accumulation in the neck while supine. Prevalence of OSA in congestive heart failure is likely to rise because of the emerging epidemic of obesity. Untreated OSA is associated with an increased risk of death independently of confounding factors in patients with congestive heart failure (54).

Stroke. Prevalence of breathing alterations during sleep is higher in patients with acute ischemic stroke or transient ischemic attacks (50% to 70%) than in the general population, both because stroke may favor occurrence of OSA and because OSA may be a risk factor for stroke, hence, there might exist a bidirectional relationship between the two. This should be considered when assessing and treating stroke patients. Studies show change in a later part of REM is associated with more incidence of stroke, suggesting some mechanism relating the two (06). A meta-analysis showed that patients with recurrent stroke had higher percentage of sleep related breathing disorders as compared to patients with an initial stroke (74% compared to 57%), suggesting sleep studies need to be performed in all stroke patients (51).

Central sleep apnea and central periodic breathing or Cheyne-Stokes breathing may appear in up to 30% to 40% of acute stroke patients, reflecting a new-onset stroke-associated condition. In the transition from the acute to the subacute phase of stroke, sleep apnea tends to improve (27), but more than 50% of patients still exhibit an apnea-hypopnea index of greater than 10/hour 3 months after the acute event because obstructive events improve less than central ones (77).

Schutz and colleagues performed a study to find the relationship between central sleep apnea and stroke (108). In a large cohort of 1346 postischemic stroke patients who underwent home apnea testing to detect central sleep apnea (defined as CAI greater than or equal to 5/hour with at least 50% of all scored respiratory events classified as central apnea), no significant relationship could be detected.

Prevention

There are no specific prevention strategies in this context. The best prevention strategy is general prevention of cardiovascular disease and early diagnosis and treatment of sleep disorders (119). Screening for OSA should be done in patients with resistant/poorly controlled hypertension, pulmonary hypertension, and recurrent atrial fibrillation after either cardioversion or ablation. In patients with New York Heart Association class II to IV of heart failure and suspicion of sleep-disordered breathing or excessive daytime sleepiness, a formal sleep assessment is reasonable and needed to distinguish obstructive sleep apnea from central sleep apnea. In patients with tachy-brady syndrome, those with ventricular tachycardia, or survivors of sudden cardiac near-death in whom sleep apnea is suspected after a comprehensive sleep assessment, evaluation for sleep apnea should be considered. After stroke, clinical equipoise exists with respect to screening and treatment. Therefore, clinical trial enrollment should be offered when possible. Patients with nocturnally occurring angina, myocardial infarction, arrhythmias, or appropriate shocks from implanted cardioverter-defibrillators may be especially likely to have comorbid sleep apnea (126).

Diagnostic workup

The diagnostic work-up for sleep disorders and, in particular, for sleep-disordered breathing in patients with cardiovascular disorders should start with a careful history and physical exam, which are fundamental in choosing the most appropriate laboratory and diagnostic tests (92; 93).

It is important to take a thorough history of sleeping habits like duration, quality, nighttime awakenings, and daytime sleep. Snoring and excessive daytime sleepiness are the most common presenting symptoms of OSAS. On awakening, patients do not feel refreshed. It is often difficult for them to get out of bed, and they may describe themselves as “slow starters.” Some feel mentally dull, groggy, confused, or disoriented. The mechanisms determining excessive daytime sleepiness in sleep apnea patients are still not completely clear. Impotence or reduced libido is sometimes reported by OSAS patients, and a study showed that testosterone and sex hormone–binding protein levels presented significant negative correlations with baseline OSAS severity (38). Irritability, depression, and morning headaches are other common clinical manifestations of OSA. Some patients complain of the need for frequent nighttime urination or of nocturnal enuresis. Heartburn or other symptoms of gastroesophageal reflux may be present if the repeated episodes of negative intrathoracic pressure associated with apneas lead to passage of gastric contents through the lower esophageal sphincter. Heavy nighttime sweating is an occasional complaint. Restless sleep is another characteristic feature of sleep apnea. The restlessness is caused by the arousals, which may be accompanied by jerks, twitches, and flailing arm movements. Restlessness is usually the spouse's complaint, whereas the patient rarely has much recollection of the arousals.

On physical examination, increased weight, increased neck circumference, and high blood pressure are common findings. Examination of the head and neck may reveal mandibular hypoplasia, craniosynostosis, or retrognathia. Allergic rhinitis and associated mucosal edema may compromise nasal patency and contribute to nasal obstruction and chronic mouth breathing, which are common in persons with sleep apnea. Common oropharyngeal findings include an elongated soft palate and uvula; a high-arched palate; edema and erythema of the peritonsillar pillars; uvula, soft palate, or posterior oropharynx; redundant pharyngeal mucosa; enlarged tongue; and enlarged tonsils. An enlarged thyroid or prominent fatty infiltration of the neck suggests that excess retropharyngeal adipose tissue is contributing to upper airway obstruction during sleep. However, most of these cases are clinically unsuspected because the two most common symptoms of loud snoring and a tendency to fall asleep during the daytime are often considered normal variants by patients who may not seek medical attention.

An increased hematocrit should suggest chronic cyanosis and hypoventilation. Other lab tests like arterial blood gases, drug and toxicity screen, and iron studies are also useful. A meta-analysis showed raised C-reactive protein (CRP) levels in a nonsmoking OSA population (68). Chest x-ray is mandatory and will establish cardiomegaly, an essential indication of heart failure. An overnight oximetry using a probe can also evaluate continuous heart rate and blood oxygen levels, which can further indicate the chances of patient having nocturnal breathing disorder. An ECG will establish whether there is hypertrophy of either or both ventricles if systemic or pulmonary hypertension has developed. If auscultation, chest x-ray, or ECG is abnormal, the next step is an echocardiogram. If heart failure is not clearly present, a blood test for brain natriuretic peptide may confirm failure when elevated, but without an echocardiogram, elevation does not rule out diastolic impairment of the left ventricle, particularly in the obese. Another blood test for prediction of the presence of cardiovascular disease is serum gamma-glutamyl transferase. On echocardiogram, diastolic function should be evaluated, whereas systolic function is derived from an ejection fraction that should be greater than 55.

The high prevalence of OSAS has focused attention on simplified approaches to diagnosis, and there is an increasing trend towards diagnosis and therapy in the ambulatory setting. Although polysomnography remains the gold standard for diagnosis, such studies are resource-intensive as they generally require the facilities of a full sleep laboratory and a trained technician. An increasing number of limited diagnostic systems are available to meet the high clinical demand, and ongoing research is directed at identifying novel signals in order to simplify and improve the diagnosis of OSAS in the home setting (92; 93).

Blood pressure in OSA patients. Different methods have been used to study blood pressure in OSA patients, each with advantages and disadvantages. Clearly, the simple measurement of office blood pressure, performed according to current guidelines, is useful in identifying patients with stable hypertension, but is insufficient to provide information about the complex alterations in the 24-h blood pressure profile found in OSA patients. The evening-to-morning change in blood pressure has been used as a marker of nocturnal hypertension in OSA patients, but results have varied according to BMI, systolic or diastolic blood pressure, or sex. A study used this method, together with catecholamine, cortisol, and cholesterol levels, and obesity assessment, to study the pathogenetic role of these factors in OSA-associated hypertension.

Blood pressure monitoring over 24 hours (ambulatory blood pressure monitoring) or during the night has allowed the study of the positive correlation between mean blood pressure over 24 hours, particularly during nighttime sleep, and OSA severity. However, ambulatory blood pressure monitoring–related sleep disturbance may affect the nocturnal blood pressure profile, although these disturbances do not appear to disrupt the physiological nighttime blood pressure reduction in most patients. OSA can be associated with nocturnal ‘‘nondipping’’ of blood pressure. Nondipping is common in OSA and can contribute to the increased cardiovascular risk in OSA patients. A nondipping pattern was found in 48% to 84% of patients with OSA, and its frequency increased with OSA severity (92; 93). The nondipping pattern was not consistently associated with daytime hypertension, as it occurred in 50% of normotensive and 43% of hypertensive OSAS patients.

High blood pressure values recorded by ambulatory blood pressure monitoring during sleep should raise the suspicion of OSA in hypertensive patients. A study of hypertensive subjects selected on the basis of a nondipping pattern at ambulatory blood pressure monitoring reported that 10 out of 11 patients had an AHI greater than 10, in agreement with data indicating a high prevalence of nocturnal hypertension in subjects with suspected OSA. OSA is a known cause of masked hypertension, defined as high blood pressure values recorded by ambulatory blood pressure monitoring in subjects with normal office blood pressure. Masked hypertension is associated with a higher risk of cardiovascular events and with target organ damage, which may progress if patients are left untreated.

Important information on the blood pressure changes occurring in OSA patients can also be obtained by using home blood pressure monitoring techniques, which, although unable to quantify nocturnal blood pressure levels, are more easily available at a lower cost than ambulatory blood pressure monitoring.

Blood pressure is rarely measured by invasive means nowadays, given the availability of noninvasive techniques. Beat-by-beat noninvasive blood pressure monitoring during sleep or 24 hours by sophisticated devices equipped with finger blood pressure cuffs coupled with a photoplethysmograph allows a more accurate analysis of blood pressure variability during daytime and nighttime compared to ambulatory blood pressure monitoring. Mean blood pressure during sleep was found to be increased in OSA patients, and postapneic hypertensive peaks correlated with the severity of nocturnal hypoxemia in patients with moderate-to-severe OSA.

In summary, some of the variability in results reported in the literature on blood pressure in OSA can be attributed to the measurement technique used to assess hypertension. In OSA patients, repeated measurements during 24 hours, either by ambulatory blood pressure monitoring or noninvasive beat-by-beat monitoring, allow the blood pressure profile to be defined during both wakefulness and sleep (92; 93).

Management

Management of OSA.

Lifestyle changes. Lifestyle changes should be considered as an integral part in the management of all patients with OSAS, including OSAS with cardiovascular diseases, as obesity and a sedentary lifestyle are very common in such patients. Patients with mild OSAS may be adequately managed by this intervention alone. Patients with mild OSA should be instructed to avoid sleeping in the supine position when polysomnographic recordings demonstrate OSA events to occur in such a posture. Supine position distractor devices can be used in such patients. In recent years, mandibular advancement devices are also being used, which advance the lower jaw and prevent obstruction of the airway during sleep. Excessive daytime sleepiness associated with OSA also affects quality of life. A randomized controlled trial showed that solriamfetol, a dopamine-norepinephrine reuptake inhibitor, improves daytime sleepiness in OSA as well as quality of life (107).

Ethanol intake increases the frequency and duration of apneas because of the combined effects of reducing upper airway muscle tone and depressing the arousal response. It is also known that moderate to heavy alcohol consumption may lead to a blood pressure increase, both in normotensive and in hypertensive subjects. It has been suggested that a reduction in alcohol intake might help in reducing both OSA severity and its blood pressure effects.

It remains unclear why hypertension in obese subjects with OSA appears to be proportionally resistant to weight loss in spite of the pronounced effects on OSA severity. One possibility is that obesity, hypertension, and OSA share a common trait that characterizes at least a subgroup of patients with sleep-disordered breathing. An additional factor to be considered is the type of blood pressure measurement used. Only in a minority of cases was objective and reproducible blood pressure measurement employed, such as home and ambulatory blood pressure monitoring. Other factors potentially interfering with the blood pressure effects of weight loss and reduction in OSA severity include duration of hypertension and occurrence of target organ damage because the occurrence of structural cardiovascular changes in patients with long-lasting hypertension might make the blood pressure elevation less sensitive to a nonpharmacological treatment.

The possibility of specific exercise programs targeting the upper airway dilating muscles has been considered, but there are no objective data to support the efficacy of such an approach. Nonetheless, regular aerobic exercise training has been reported to be associated with a blood pressure reduction in hypertension (92; 93).

Antihypertensive drugs in hypertensive patients with OSA. The choice of antihypertensive medications in hypertensive patients with concomitant OSA may have specific implications for their optimal clinical management. The effects of antihypertensive agents on OSA activity are not uniform. Only a few studies have compared different agents through parallel group or crossover designs. Unfortunately, statistical power was usually poor due to low patient numbers. Although a decline in OSA severity may be associated with blood pressure reduction, such a reduction may also be possibly related to a direct effect of the drug itself. Finally, effects of long-term treatment with certain antihypertensive agents on OSA severity have never been systematically addressed during clinical trials. In general, there is no obvious antihypertensive drug class that has repetitively demonstrated superior antihypertensive efficacy in OSA patients. Additional clinical research is needed in order to identify preferred compounds for an adequate blood pressure control in this group of high-risk patients (92; 93).

A randomized cross-over study that included 13 male patients with hypertension and moderate to severe OSA showed acetazolamide alone and in combination with CPAP lowered the mean baseline blood pressure -7 (95% CI, -11 to -4) and -4 (95% CI, -11 to -4), respectively (33).

A meta-analysis that included 28 studies was done to see the effect of acetazolamide in OSA patients and compare it with CSA patients. Results showed that acetazolamide versus control lowered the apnea hypopnea index by -0.7 (95% CI, -0.83 TO -0.58). The apnea hypopnea index reduction was similar in the CSA group and significantly greater at high doses. It also improved oxygen saturation nadir by +4.4% (95% CI, 2.3 to 6.5) and several secondary outcomes that included sleep quality measures and blood pressure (105).

CPAP treatment in OSA patients with hypertension. Many studies have assessed the impact of active therapy of OSA on blood pressure levels, both in normotensive and hypertensive patients, with variable results. The various reports have employed widely different methodologies, ranging from short-term placebo-controlled protocols to long-term observational studies. A review study that assessed the endothelial function in OSA patients post-CPAP concluded that CPAP significantly decreases inflammation, improves blood flow, increased arterial elasticity, and decreases stiffness, hence, reducing cardiovascular risk in patients with OSA (14). In another study that compared the effect of CPAP, mandibular advancement device (MAD), and no treatment on lowering the blood pressure in OSA patients at the end of 1 year showed that both CPAP and mandibular advancement device group had significantly lower apnea hypopnea indexes, but no difference was found in all three groups with regards to 24-hours ambulatory blood pressure monitoring (44). Hence, the results are conflicting. Despite the widely differing methodologies, the overall findings of these reports is that CPAP therapy in OSA results in a lowering of blood pressure levels, which is most pronounced when assessed by ambulatory blood pressure monitoring and in patients with severe OSA that regularly use CPAP every night for at least 5 hours/night, and who have preexisting hypertension. The benefit affects both systolic and diastolic blood pressure and is evident both during wakefulness and sleep.

As far as the impact of CPAP on visceral adipose tissue reduction is concerned, a meta-analysis of randomized controlled trials showed that CPAP does not lead to reduction of visceral adipose tissue irrespective of therapy duration (19).

More evidence is available on the more pronounced effect of CPAP treatment on blood pressure values in patients with resistant hypertension (35).

Daytime sleepiness as a factor associated with OSA and hypertension is not a new finding. Although it has been debated whether CPAP therapy improves blood pressure control in nonsleepy patients, a report by Barbé and colleagues indicates a significant benefit of long-term CPAP therapy in OSA patients on blood pressure levels, even among nonsleepy patients (07). Several meta-analyses of studies of CPAP therapy effects on blood pressure in OSA patients have been published in recent years (92; 93; 34). One of the latest meta-analyses evaluating the effect of OSA treatment on blood pressure attempted to study predictors of blood pressure reductions: the analysis of data from 68 randomized controlled trials showed that the overall effect of OSA treatment on blood pressure was modest but was more pronounced in patients younger than 60 years old, with high blood pressure at baseline and with more severe OSA-related nocturnal hypoxia (95).

Other OSA treatments. Compliance is the main problem with most of the studies that focused on the effect of CPAP on OSA. Getting the satisfactory compliance with CPAP is challenging. There is a need for interventions to improve adherence and tolerance. The alternatives to mild to moderate OSA can be mandibular advancement devices, positional therapy, and hypoglossal nerve stimulation. More research is needed to find better tolerated alternatives to CPAP (37).

The use of mandibular advancement device has been shown to be effective in treating OSA and also in reducing BP levels in randomized controlled trials (95).

Neurostimulation for OSA using ansa cervicalis stimulation with or without hypoglossal nerve stimulation showed increased maximum inspiratory flow rate and can be a possible targeted treatment for OSA (56).

Limited evidence is available on the effects of OSA treatment through surgical procedures like transoral robotic OSA surgery or through use of oral appliances on blood pressure, an issue that deserves to be addressed in future studies. Very preliminary data are available on the effects of renal sympathetic denervation, through catheter ablation technique in OSA patients, suggesting a reduction of elevated blood pressure of OSA severity and on glycemic control in patients with resistant hypertension (92; 93).

Management of sleep-related breathing disorder in stroke. Several publications suggest that CPAP treatment could have favorable effects in stroke patients with OSA (18). An observational study done to recognize long-term effect of CPAP treatment on cardiovascular function in patients with OSA showed that those who were not prescribed CPAP or did not remain adherent had a significantly higher incidence of cerebrovascular events with p<0.05 but not higher incidence of cardiovascular events (90). Despite this, CPAP acceptance represents a major problem in treating this type of patient. Previous studies have documented that only about 50% (45% to 70%) of patients can be put under CPAP treatment after stroke, an only 15% remain under treatment during a 6-year follow-up. In a study of patients with ischemic stroke, CPAP was offered to 58% of patients and at the end of 7 years of follow-up, those who did not remain adherent to CPAP saw three times increase in recurrent stroke or cardiovascular events. Very few data exist about CPAP treatment during acute stroke, but CPAP treatment can be considered individually, mainly in patients with mild-moderate neurologic deficits, moderate-severe OSA (apnea hypopnea index greater than 30/h), and high cardiovascular risk profile. BiPAP is also an alternative in those patients who do not tolerate CPAP.

In patients presenting predominantly with central apneas or central periodic breathing, oxygen may be beneficial. The benefit of CPAP treatment in stroke patients with central apneas or central periodic breathing has not yet been proven. A novel method of ventilator support called ‘‘adaptive servo-ventilation’’ was shown to prevent central apneas in stroke patients with heart failure more efficiently than CPAP or oxygen. There is a need for more extensive research on the use of CPAP in CSA in stroke patients as most of the studies that exist right now are derived from use of CPAP or other techniques like phrenic nerve stimulation, or acetazolamide in treating central apnea in heart failure patients (98).

Management of sleep-related breathing disorder in heart failure.

Patients with heart failure and OSA.

In patients with congestive heart failure, the ratio of minute ventilation over CO2 (VE/CO2) was assessed in patients with OSA. During exercise, VE/CO2 slope correlated positively with the severity of OSA, suggesting that rising CO2 response should point towards underlying OSA, which is a treatable disorder and can reduce congestive heart failure mortality (11).

Drugs. Pivotal treatment of heart failure is the use of diuretic agents. In a small short-term interventional study, 15 patients with severe OSA and hypertensive etiology of diastolic heart failure were hospitalized to receive furosemide 20 mg and spironolactone 100 mg twice daily for 3 days. Before and after the intervention polysomnography to assess AHI, acoustic pharyngometry to assess oropharyngeal junction area and spirometry to calculate the ratio between forced midinspiratory flow and forced midexpiratory flow were performed. Beyond the significant decrease in body size among participants, there was also a decrease in AHI by 17 episodes/h, an increase of oropharyngeal area by 55 cm2, and decrease of the combined spirometric measure by almost 25%. The findings of this study confirm the pathophysiological role of peripharyngeal edema in the development of OSA in heart failure patients and also suggest that pharmacological treatment of heart failure with diuretics may reduce the severity of OSA, despite the fact that heart failure patients did not demonstrate impaired systolic function and fluid retention. We can hypothesize that patients with fluid retention and systolic heart failure could similarly benefit from diuretic agents for all of the above measures as in those with hypertension-mediated diastolic heart failure. However, in cases of more severe heart failure further complicated with increased disease burden, the effect of pharmacological treatment on OSA might be different and also detrimental (eg, inappropriate reduction of left ventricle filling pressures).

Clinical trials have shown that sacubitril/valsartan has a beneficial effect in heart failure with reduced ejection fraction; thus, it is hypothesized to have an effect on sleep-disordered breathing. However, the data from the AWAKE-HF trial showed that sacubitril/valsartan therapy when compared with enalapril alone did not significantly improve sleep-disordered breathing, sleep duration, or efficiency (91).

Exercise rehabilitation. Exercise rehabilitation programs represent beneficial therapeutic measures to increase exercise capacity in patients with heart failure. Eight patients with OSA underwent a 4-month period of supervised exercise training (3 sessions per week, 60 min for each session) after a 4-month attended nontraining period. AHI was reduced by almost 12 episodes/h after the training phase of the study when compared to AHI detected at end of the 4-month nontraining period. Also, a significant decrease in muscle nerve sympathetic activity was observed during the same study timeframe.

Atrial overdrive pacing. Although atrial overdrive pacing does not have a discrete therapeutic position in the management of heart failure, it has been hypothesized that suppressing the periods of bradycardia associated with apnea may reduce autonomic imbalance in OSA. OSA regression was examined in 15 patients with mild impairment of systolic function (baseline ejection fraction ranging from 40% to 56% for 73% of the entire cohort) and a previously implanted permanent pacemaker. Seven patients were predominantly affected by OSA; however, all patients demonstrated both obstructive and central apneas. By examining all OSA events in this cohort, the effect of atrial overdrive pacing (pacing rate was set 15 bpm above the basal heart rate) was associated with significant reduction of AHI with respect to baseline (no pacing phase). Although the pathophysiological mechanism of this phenomenon is not yet clear, it has been hypothesized that reducing the variability in cardiac output with cardiac pacing may stabilize respiratory output, and possibly stabilize pharyngeal caliber, because upper airway caliber oscillates in synchrony with fluctuations in respiratory output. Above and over this ambitious hypothesis, a Hellenic study provided different results as compared to the study by Garrigue and colleagues (42). A cohort of 16 nonheart failure (mean ejection fraction 59%) patients with a permanent pacemaker was followed for 2 months, and in this timeframe, was randomized twice (crossover, two groups of eight patients) to receive 1 month of atrial overdrive pacing and 1 month CPAP treatment. Although CPAP effectively reduced the severity of OSA, atrial overdrive pacing treatment failed to achieve a similar result. Besides the findings from the Hellenic study including nonheart failure patients, an additional study examined the effects of atrial overdrive pacing in patients with and without heart failure. Atrial overdrive pacing did not ameliorate AHI independently of baseline ejection fraction. A final study by Sharafkhaneh and colleagues in the same clinical setting examined a pure population of OSA patients with heart failure (mean ejection fraction 38%) (109). Although those undergoing atrial overdrive pacing demonstrated a 50% reduction of AHI (from 34.8 to 18), patients undergoing basal pacing (40-50 bpm) did not have a significantly different reduction of AHI (from 34 to 24). Taken together, atrial overdrive pacing is not associated with improvement of OSA, both in heart failure and in nonheart failure patients (02).

Resynchronization therapy. Cardiac resynchronization therapy by increasing the cardiac output in patients with heart failure and OSA could reduce fluid retention and edemas in the peripharyngeal tissues. In a meta-analysis of three studies of patients with OSA, left ventricular ejection fraction was increased over a follow-up period of 23 weeks. However, the improvement of cardiac performance was not associated with significant change in AHI. Because baseline and posttreatment ejection fraction was 25% and 31%, respectively, the increase in cardiac output could be insufficient to adequately counterbalance fluid retention. Taking into consideration that heart failure and OSA both share the obese phenotype and its consequent circulating volume overload, electrical therapies that have no impact on volume overload might not be effective in treating OSA.

Renal sympathetic denervation. Renal sympathetic denervation was proposed as an alternative (“upstream”) treatment for OSA in patients with treatment-resistant hypertension. Ongoing trials of renal sympathetic denervation are currently recruiting patients with heart failure under the hypothesis of efferent sympathetic firing reduction that, in turn, would have beneficial effects on cardiac function. Although the effects of renal sympathetic denervation in 10 patients with OSA were encouraging, several concerns dispute the merit of these findings (124).

Continuous positive airway pressure. Investigators aimed to assess the therapeutic impact on nighttime changes of intrathoracic pressure and afterload levels using 1-night CPAP application in eight patients with heart failure (ejection fraction < 45%). Patients underwent assessment of these measures before sleep and during stage 2 of sleep 1 day before CPAP application, the day of CPAP application, as well as 1 day afterwards. Although afterload increased all three nights of the examination at stage 2 of sleep compared to the pre-sleeping period, this increase was more than 2-fold reduced during the CPAP application, compared to the pretreatment and posttreatment nights. Additionally, the magnitude of negative intrathoracic pressure swings by the comparison of before-sleep levels and levels observed at stage 2 of sleep was found reduced by almost 6-fold during the night of CPAP application compared to the previous night and by almost 4-fold compared to the following night.

Twenty-four patients (mean age 55 years, 90% men) with stable heart failure (ejection fraction < 45%, mean 27%) and prevalent OSA (AHI > 20, > 50% overnight obstructive episodes) were randomized to CPAP treatment and non-CPAP (controls) for a short period of 1 month. Systolic blood pressure and heart rate decreased significantly in the group receiving 1-month CPAP therapy compared to baseline, whereas these measures did not change in the control group, suggesting that CPAP was beneficial in reducing the overall workload of left ventricle. Additionally, left ventricular ejection fraction demonstrated a relative increase by 9% in the CPAP group compared to controls (P < 0.001), with a within-CPAP group ejection fraction increase from baseline of 35% (from 25% at baseline at 33.8% at 1 month).

In another small cohort of 17 patients (mean age 53 years, 90% men) with heart failure (mean ejection fraction 30%) and prevalent OSA (AHI > 20, > 50% overnight obstructive episodes), it was investigated whether CPAP treatment reduces daytime sympathetic activity, as assessed by muscle sympathetic nerve activity over a period of 1 month. Sympathetic activity demonstrated a significant relative reduction (between-groups comparison), whereas the same measure in the group of CPAP patients also decreased significantly at 1 month compared to baseline levels (P = 0.009 and P < 0.001, respectively). Additionally, beyond the reduction of sympathetic tone, systolic blood pressure levels decreased significantly, suggesting that CPAP may remove this apnea-induced stimulus to sympathetically mediated vasoconstriction. Finally, left ventricular ejection fraction demonstrated a trend to increase at 1 month compared to baseline levels (from 32.1% to 38.3%, P = 0.06).

Midterm (3-month) effects of CPAP on left ventricular function were examined in a randomized cohort of 55 patients (mean age of 57 years, 90% men) with heart failure. Patients at baseline demonstrated less impaired systolic function (mean ejection fraction 35%) and less severe OSA (mean AHI of 28, > 80% overnight episodes were of obstructive origin) compared to the previously examined cohorts. Left ventricular ejection fraction was significantly increased in the CPAP group compared to controls (P = 0.04), whereas left ventricular ejection fraction was also increased compared to baseline levels in those receiving a 3-month CPAP treatment (from 37.6% to 42.6%, P < 0.001). In the same study, patients under randomization underwent urine norepinephrine measurements at baseline and at end follow-up. The levels of this measure of sympathetic activity decreased significantly compared to baseline levels in patients randomized to CPAP, whereas the control group did not demonstrate any significant change.

Regarding the long-term effects of CPAP on mortality, 14 of 51 patients with heart failure (ejection fraction 25%) and at least moderate OSA were treated in a nonrandomized manner with CPAP for a mean period of almost 3 years, but without recording of “wear-on” mask time. Importantly, there were no deaths during the whole follow-up period in the group of heart failure patients with treated OSA. Early mortality (before 3 months) in the untreated OSA group (n = 35) was 5.5%, whereas long-term mortality (after 3 months) was 20%. Overall, there was a trend in favor of the treated arm to improve survival (P = 0.07). Moreover, due to the small sample size of treated heart failure patients, definitive conclusions for potential beneficial effects of CPAP on survival rate in heart failure patients with OSA cannot be confirmed. However, this study reported mortality data for the impact of CPAP on heart failure patients in both sexes because previous evidence focused only on nonheart failure men.

The results of a study on administrative insurance claims data showed that PAP therapy adherence in patients with OSA with heart failure with reduced ejection fraction was associated with a reduction in health care resource utilization, further supporting the use of CPAP in patients with heart failure (76).

Finally, a cohort of 88 patients (mean age 60 years, 90% men) with heart failure (mean ejection fraction 36%) and at least moderate OSA (mean AHI 43, > 50% overnight episodes were of obstructive origin) received CPAP or no treatment in a nonrandomized manner for a mean period of 2.1 years. The composite of death and hospitalizations for heart failure was examined along with intervention (65 patients received CPAP and 23 patients remained untreated). The event-free survival rate was 2.4-fold higher in the CPAP group compared to controls. Of note, presence of ischemic heart failure, presence of atrial fibrillation, and functional class NYHA III qualified as significant categorical determinants of the outcome after adjustment for confounders beyond the categorical variable “untreated obstructive sleep apnea.” By focusing on patients who received CPAP during the follow-up period, 32 and 33 patients were classified as compliant and noncompliant to treatment, respectively. The event-free survival rate was 3.1-fold higher in the compliant group compared to their noncompliant counterparts, suggesting that the mask “wear-on” time might be an important efficacy modulator of the outcome (53; 116).

Flow-targeted dynamic bilevel positive airway pressure support (adaptive servo-ventilation) was introduced as treatment in 31 patients with heart failure (reduced ejection fraction) and sleep apnea, both central and obstructive ones. After the results of the SERVE-HF study, patients with central apneas and reduced ejection fraction seem to have no benefit from treatment with ASV; conversely, more evidence is needed, especially in pure cohorts of OSA and heart failure.

Taken together, the answer to the introductory question of this section could not be definitive. Indeed, the statistical power of the studies and the sample size create misgivings for safe interpretation of the results. Adequately powered randomized trials to assess the impact of CPAP on heart failure prognosis, including intermediate clinical endpoints, are urgently needed (12; 21; 54; 83; 86; 110).

Automatically titrating CPAP (APAP) is a device that functions by adjusting delivery pressure of air to the patient’s individual needs. It can deliver air at lower pressures, which benefits patients in terms of cardiac filling. The RCT SAVE (Sleep Apnea Cardiovascular Endpoint) trial concluded that it does not significantly improve cardiovascular mortality. In the trial, the device was used only for 3.5 hours/night, which is insufficient time to note any changes. A trial done in patients with heart failure with reduced ejection fraction showed that APAP intervention significantly improved the cardiovascular outcomes represented by peak VO2. In this trial, 76 patients were randomized into the APAP group and control group (nasal strip) for 6 months. At the end, VO2 was increased (67+/- 17 to 73+/-19%; p=0.01). There was also an improvement seen in left ventricular function, hypoxemia, and quality of life in APAP group. Further larger studies are required to comment more on the use of APAP in heart failure patients with OSA (36).

Neuromodulation. Hypoglossal nerve stimulation is being used increasingly for the treatment of severe OSA in patients who cannot tolerate CPAP or are nonadherent. Invasive electrical stimulation has been trialed in randomized controlled studies demonstrating efficacy in reducing OSA severity and related symptoms (115). Nevertheless, it represents an invasive procedure that requires hospitalization and sleep endoscopy to identify responders. Noninvasive techniques are available and showed similar effectiveness in reducing OSA severity, particularly in responders (97; 10).

Several other devices have been tested and show encouraging results, both in terms of feasibility and effectiveness, making the field of neuromodulation a possible alternative treatment for OSA (106). More studies are needed confirming the positive results in a real-world setting. No data are available on the use of such treatments in OSA patients with heart failure.

Patients with heart failure and central sleep apnea.

Drugs. Theophylline has a stimulating effect on the central nervous system, including the respiratory drive. The hypothesis of whether theophylline might be accompanied by beneficial effects on both central sleep apnea and heart failure was examined previously. In a double-blind, randomized, placebo-controlled study, 15 patients with heart failure were randomized to receive theophylline or placebo with a crossover design over a period of 1 week. At the end of the study, AHI was reduced by almost 50%, whereas central apneic phenomena almost disappeared. No effect was observed regarding the action of the drug on obstructive phenomena. Although the exact pathophysiological mechanism for the beneficial effects of theophylline is unknown, the available clinical data for long-term efficacy and safety are rather limited. Moreover, long-term drug-induced arrhythmogenesis should be excluded before any recommendation in favor of theophylline.

Acetazolamide is a mild diuretic and stimulant of the respiratory drive. It has also been used in the treatment of high-altitude central sleep apnea and in subjects prone to mountain sickness. A double-blind randomized trial in healthy subjects demonstrated that blood pressure increase after acute exposure at high altitude can be counteracted by acetazolamide (93). Acetazolamide was administered once daily 1 hour before bedtime over 1 week in 12 patients (66 years, 100% men) with heart failure (ejection fraction 20%) under stable hemodynamic conditions. AHI was reduced by 38% and central apneas by almost 50%. There was no significant impact of the treatment on OSA phenomena. Long-term safety and efficacy results in heart failure patients are lacking.

A Cochrane review concluded that the use of pharmaceutical therapy in the treatment of central sleep apnea is not sufficiently supported by the available research; thus, more studies are required to assess the effects of pharmacological therapies, particularly over a longer period (101).

Supplemental oxygen. It was evaluated whether the application of supplementary oxygen (2 L/min by nasal cannula) was equally effective to CPAP (9 ± 0.3 cmH2O) in reducing the severity of central sleep apnea in a small cohort of nine patients with severe heart failure (baseline ejection fraction 17%) and central sleep apnea (baseline AHI 45). Both supplemental oxygen and CPAP were associated with the same extent of AHI reduction (18 vs. 16 episodes/h, respectively). By contrast, total sleep time and sleep efficiency were significantly higher in the CPAP night compared to the supplemental oxygen night, suggesting that sleep quality during the non-CPAP night was more impaired. Under the hypothesis of upper airway unrestrained patency, supplemental oxygen might contribute to ventilatory stability in central sleep apnea. However, we should acknowledge that heart failure patients frequently experience sleep apnea of both types, with the obstructive phenotype being unresponsive to supplementary oxygen.

Exercise rehabilitation. Nine patients (mean age 60 years, 80% men) with heart failure (ejection fraction 30%) and central sleep apnea (baseline AHI 40) underwent a 4-month period of supervised exercise training (3 sessions per week, 60 min for each session) after a 4-month attended nontraining period. No significant impact was observed on central sleep apnea severity, sleep pattern, and muscle nerve sympathetic activity in these patients undergoing exercise rehabilitation. In another small cohort of 18 patients with heart failure and central sleep apnea, 6-month aerobic exercise training was accompanied by increased exercise capacity and improvement of central sleep apnea (3-fold reduction of both AHI and number of central apneas compared to baseline levels). The divergent results between these studies might be related to the different monitoring implemented for sleep apnea evaluation, and to the different type or intensity of training. More studies are needed to clarify this issue because cardiac rehabilitation in heart failure is associated with improvement of cardiac performance and pulmonary decongestion.

Atrial overdrive pacing. Atrial overdrive pacing has been tested as an alternative therapeutic option in patients with a permanent pacemaker to reduce the severity of central sleep apnea in heart failure. During central sleep apnea, there is a parasympathetic activation associated with bradycardia, blood pressure reduction, and increased heart rate variability. Reducing heart rate variability with atrial overdrive pacing may have a positive impact on central sleep apnea. In patients with heart failure and a permanent pacemaker, a significant reduction of AHI compared to baseline levels was observed. However, there is no comparative study between atrial overdrive pacing and CPAP in heart failure patients. More studies are needed to evaluate whether atrial overdrive pacing ameliorates central sleep apnea in heart failure patients. However, this eventual option might be strictly reserved to patients with a permanent pacemaker.

A meta-analysis of 15 studies evaluating 440 patients with CSA showed that atrial override pacing was associated with significant reduction in apnea hypopnea index, but the magnitude of reduction was small (118).

Resynchronization therapy. A meta-analysis including studies with central sleep apnea reported a clear beneficial effect of resynchronization therapy on central sleep apnea severity (63). The reduction of AHI in all included studies was 13 episodes/h (P < 0.001); there was a parallel significant increase in left ventricular ejection fraction. The effect of atrial overdrive pacing on top of resynchronization therapy in sleep apnea patients with predominant central sleep apnea demonstrated a trend toward statistical significance compared to resynchronization alone (P = 0.07). Cardiac resynchronization therapy has shown efficacy in improving CSA in patients with pacing-induced cardiomyopathy. In a cross-over study, resynchronization therapy was compared to right ventricular pacing in patients with heart failure (08). Overall, there was a significant decrease in apnea hypopnea index in cardiac resynchronization therapy group versus right venous sampling.

Cardiac transplantation. Restoring cardiac function with heart transplantation might change the physical history of central sleep apnea. In a prospective controlled trial, 22 patients with final stages of heart failure and scheduled for heart transplantation underwent polysomnography before and 6 months after surgery. Heart transplantation reduced the severity of sleep apnea in those with central sleep apnea before surgery. However, sleep apnea phenomena did not disappear despite the normalization of sympathetic activity as assessed with sympathetic nervous system markers measured before and 6 months after the procedure. Also, the type of sleep apnea after transplantation was not exclusively of central type and, interestingly, obstructive phenomena were prevalent in most patients with sleep apnea after surgery.

Continuous positive airway pressure. Naughton and colleagues examined the acute effects of CPAP treatment on cardiac afterload and intrathoracic pressure levels in 15 heart failure patients compared to nine healthy controls (89). Graduated CPAP from 0 to 10 cmH2O was administered over a period of 75 minutes in the two groups of participants, followed by a control period of the same timeframe of the intervention. The inspiratory muscles generated greater force per breath, and systolic intrathoracic pressure contributed more to left ventricular transmural pressure in patients with heart failure than in healthy subjects. By increasing intrathoracic pressure in patients with heart failure, CPAP unloaded inspiratory muscles and reduced left ventricular afterload without compromising cardiac index. This finding of left ventricular unload with CPAP was confirmed in another study in which the use of CPAP in heart failure patients with central sleep apnea reduced mitral valve regurgitation and decreased brain natriuretic peptide. Finally, it was also demonstrated that patients with heart failure and central sleep apnea have greater nocturnal urinary and daytime plasma norepinephrine concentrations than heart failure patients without central sleep apnea and that attenuation of central sleep apnea with CPAP reduced the concentrations of these measures. These promising results constituted a plausible background to design randomized trials for the role of CPAP on heart failure prognosis in the long term.

The prognostic role of central sleep apnea on the combined endpoint of mortality and cardiac transplantation rate was examined in a prospective cohort of 66 heart failure patients (29 with central sleep apnea) who underwent randomization to treatment with CPAP or no treatment (control group) and were observed for a mean period of 2.2 years. The application of CPAP was associated with a 50% relative risk reduction of the combined endpoint compared to controls; however, this finding was not statistically significant (P = 0.101). When the two CPAP-intolerant patients were excluded from the analysis, the relative risk reduction for treated compared to untreated heart failure patients escalated to 60% (P = 0.047). Finally, among heart failure patients receiving CPAP treatment, those with central sleep apnea were at a higher risk of the adverse combined outcome compared to those without central sleep apnea. A strong trend toward a lower rate for the combined endpoint was revealed among those randomized to CPAP compared to controls (relative risk reduction of 67%, P = 0.059).

The Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure (CANPAP) trial was a multicenter, randomized, open-label blinded-to-the-outcome trial designed to investigate the following questions: (1) whether CPAP reduces the severity of central sleep apnea; (2) whether this potential severity reduction would be translated into better outcomes in terms of morbidity and mortality (ie, transplantation-free survival); and (3) whether CPAP ameliorates cardiovascular parameters such as left ventricular ejection fraction (Bradley and Logan 2005). Eligible to participate in the CANPAP trial were heart failure patients with NYHA class between II and IV, ejection fraction below 40%, and AHI of 15% or more with greater than 50% of central apneic phenomena. Patients (mean age 63 years, 97% men, mean ejection fraction 24.5%, AHI 40) were randomized to medical therapy alone (n = 130) and CPAP on top of medical therapy (n = 128) and were observed for a mean period of 2 years. The CPAP treatment had to be applied at least 6 hours daily, and time wearing the mask was also registered. After an initial 3-month CPAP titration period, the group of patients treated with the combined regimen of CPAP and medical therapy as compared to the group treated with medical therapy alone demonstrated a greater reduction in the frequency of apnea and hypopnea episodes, as well as in norepinephrine levels, whereas left ventricular ejection fraction and exercise capacity as assessed by the walked distance in 6 minutes were significantly increased in the former group as compared to the latter. By contrast, no differences in hospitalizations and no difference in mortality rates were observed between the two groups. Interestingly, an initial divergence of the events-rates curve was observed in favor of the control group, suggesting that CPAP might have an early adverse effect in some patients. Authors also observed that the results of the “intention-to-treat analysis” are different from the “per-protocol analysis” because dropout patients demonstrated mortality rates higher than the patients who remained randomized. Another explanation for this paradox might be the adverse effect of the relatively rapid CPAP titration, especially in patients with low filling pressures and low stroke volume due to more aggressive diuretic therapy.

A posthoc analysis of the CANPAP trial reported the comparative evaluation of patients with AHI less than 15 at 3 months (suppressed central sleep apnea group); patients with an AHI of 15 or more at 3 months (unsuppressed central sleep apnea group); and patients not receiving CPAP (control group). Heart transplantation–free survival was significantly better in the suppressed central sleep apnea group compared to controls (P = 0.034), whereas no difference in the outcome rate was observed between the unsuppressed central sleep apnea group and controls (P = 0.180). Of note, adherence to treatment did not differ between the two subgroups “on-CPAP” treatment, suggesting possible lack of efficacy or that effectively prompt treatment could be important in this clinically fragile group of heart failure patients.

Phrenic nerve stimulation. This peculiar technique was introduced to treat central sleep apnea in a small cohort of heart failure patients. Through either the left or the right brachiocephalic vein or through the pericardiophrenic vein, an overnight transvenous catheter was introduced to deliver energy and stimulate periodically phrenic nerve. AHI and arousal index were strongly decreased during the night of phrenic nerve stimulation compared to the night before the procedure. However, long-term results of the technique, possible complications due to the invasive nature of the procedure, and long-term tolerability remain to be addressed. Also, it is unknown whether the improvement of central sleep apnea dynamics will be accompanied by improvement of cardiac function parameters.

The first prospective, multicenter, randomized trial with blinded endpoints evaluating the safety and efficacy of the Remedē System has been published. This is a novel treatment that uses transvenous phrenic nerve stimulation to contract the diaphragm, showing that the mean AHI decreases from 49 to 23/hour at 3 months, with persistence of significant nighttime central sleep apnea (23).

Remedē System also appears to significantly reduce the nocturnal hypoxemic burden due to sleep-disordered breathing (09). A prospective study was done in patients with moderate to severe central sleep apnea (49). Baseline apnea hypopnea index, central sleep index, and arousal index were noted to be 40, 25, and 32 events per hour, respectively. All were recorded at 6, 12, and 18 months, respectively. The results showed improvement at subsequent visits. Quality of life also improved.

More studies are needed to establish the ideal indication of CPAP for heart failure complicated by central sleep apnea. Prompt and adequate suppression of central sleep apnea in patients with well-evaluated hemodynamics might prevent possible adverse effects of this treatment. Currently, there is not enough evidence to prescribe such treatment in heart failure patients with central sleep apnea. There is also a long way to go in the same setting for auto servo-ventilation and, possibly, phrenic nerve stimulation.

Special considerations

Pregnancy

In the general population, short sleep cycles and poor sleep quality have been linked to negative effects on cardiovascular health. Pregnancy is no different as short sleep duration and self-reported poor sleep quality as judged by the PSQI were independently linked to an elevated risk of gestational diabetes in cross-sectional studies (15). Furthermore, different sleep disorders have been connected to poor perinatal outcomes (96). Heavy snoring at night is also prevalent in pregnant women, and it may be an independent factor for poor infant outcome. A study of normal pregnant women observed during pregnancy has shown that snoring may be present during pregnancy alone, and despite the fact that blood pressure may stay within normal range, systolic pressure may increase more in women who snore loudly than in those who do not.

Pregnancy may not cause sleep related breathing disorder in otherwise healthy women. However, when a predisposing condition is present like obesity, pathophysiological changes during pregnancy may enhance or precipitate sleep related breathing disorders (41).

The benefit of nasal CPAP administration in pregnant women recognized to have hypertension early in pregnancy is associated with better blood pressure control and improved pregnancy outcomes. Indeed, nasal CPAP has been proposed as therapy for preeclampsia (92; 93).

Anesthesia

Anesthesiologic risk quantification must take into account the presence of sleep-related breathing disorder in cardiovascular patients approaching surgery more than in the general population. Evidence is still lacking on the benefits of treating OSA patients prior to surgery in different clinical settings.