Objectives

1. To describe the acute cardiovascular changes that occur with apnea.
2. To understand the pathophysiology of the acute cardiovascular changes associated with apnea.
3. To describe the chronic cardiovascular abnormalities associated with sleep-disordered breathing (SDB), with particular reference to the Sleep Heart Health Study.
4. To identify the potential pathophysiologic mechanisms underlying chronic cardiovascular disease in SDB.
5. To understand the clinical relevance of cardiovascular abnormalities in SDB.

Key words

cardiovascular disorders; cerebrovascular disorders; hypertension; pathophysiology; sleep apnea; sleep-disordered breathing

Abbreviations

AHI = apnea-hypopnea index; CI = confidence interval; CPAP = continuous positive airway pressure; HTN = hypertension; NREM = nonrapid eye movement; RDI = respiratory disturbance index; REM = rapid eye movement; SDB = sleep-disordered breathing; SHHS = Sleep Heart Health Study

Sleep-disordered breathing (SDB) is a common but underrecognized condition associated with significant adverse cardiovascular and neurocognitive consequences.¹ The spectrum of sleep-related breathing disorders defined by the American Academy of Sleep Medicine Task Force² includes the obstructive sleep apnea-hypopnea syndrome, the central sleep apnea-hypopnea syndrome, the upper airway resistance syndrome, and the sleep hypoventilation syndrome. This overview will focus on the most common form of SDB, obstructive sleep apnea, and its relationship with acute and chronic cardiovascular abnormalities. For further discussion of this topic, the reader is referred to a recent comprehensive review.³ Central sleep apnea/Cheyne-Stokes respiration associated with congestive heart failure has also been reviewed³ and will not be discussed here.

The first descriptions of SDB in the 1950s to 1970s included the Pickwickian syndrome and cases of severe SDB associated with chronic systemic hypertension (HTN) and right heart failure. Early on, investigators noted acute hemodynamic changes with apnea. Epidemiologic studies suggested a relationship between chronic sleep apnea and increased mortality⁴ and adverse cardiovascular consequences. However, many of these studies were criticized for poor research design and lack of control for confounders.⁵ The Sleep Heart Health Study (SHHS),⁶ among others, has attempted to deal with some of these issues and definitively answer the question as to whether SDB is or is not associated with cardiovascular disease independent of other factors. Significant work to help elucidate mechanisms of disease is ongoing in multiple laboratories.

Definitions

Obstructive sleep apnea syndrome is characterized by recurrent episodes of complete upper airway obstruction (apnea) or partial upper airway obstruction (hypopnea) during sleep, leading to disturbed nocturnal sleep and daytime hypersomnolence. More than 5 respiratory events per hour of sleep has traditionally been used as the cutoff between normal and abnormal, although some suggest that this cutoff should be adjusted depending on the definitions and monitoring techniques used for respiratory events⁷ and the presence or absence of symptoms. The sum of apneas and hypopneas per hour of sleep (apnea-hypopnea index [AHI]) and the sum of all respiratory events per hour of sleep (respiratory disturbance index [RDI]) are commonly used summary statistics for SDB.

Apnea is defined as a pause in breathing (absence of airflow) lasting > 10 s. Central apneas are defined by the lack of respiratory effort on chest and abdominal gauges, while obstructive apneas are defined by presence of effort. Hypopneas are defined by reduction in airflow for > 10 s, with or without a consequence such as arousal or oxygen desaturation. Respiratory effort-related arousals are characterized by increasing effort (in the absence of airflow changes that meet the criteria for an apnea or hypopnea) leading to arousal from sleep. While the definition of apnea is fairly universal, the definition of hypopnea (eg, the amount of airflow decrement required, the need for arousal, the need for desaturation, the amount of desaturation required) has varied among clinical and research laboratories,⁸ and respiratory effort-related arousals are by no means universally measured. In addition to differing definitions, techniques for monitoring airflow and effort also vary across laboratories. In response to these issues, the American Academy of Sleep Medicine Clinical Practice Review Committee⁹ has proposed a consensus definition for hypopnea similar to that used in the SHHS, although the best metric to define SDB remains controversial.¹⁰

Obstructive sleep apnea, however defined, is a common disorder. An AHI of > 5/h (using thermocouples and end-tidal carbon dioxide gauges to measure nasal and oral airflow, defining apnea as complete cessation of airflow, and defining hypopnea as discernible reduction in airflow accompanied by > 4% reduction in oxyhemoglobin saturation) was found in 24% of men and 9% of women in a population of community-dwelling middle-aged adults.¹¹ Obstructive sleep apnea syndrome, defined as an AHI of > 5/h and symptoms of sleepiness, was found in 4% of men and 2% of women in the same population. This high prevalence suggests that, even if obstructive sleep apnea causes cardiovascular disease in only a small percentage of patients, it could be a major cause of excess morbidity and mortality in the general population.

Acute Cardiovascular Changes in Apnea

In normal individuals, sleep is characterized by cyclic alterations between nonrapid eye movement (NREM) and rapid eye movement (REM) sleep approximately every 90 min, with four to six sleep cycles throughout the night. The normal drive to breathe during wakefulness is lost with the onset of NREM sleep and breathing falls under metabolic control (Table 1). Respiration is regular, with a small decrease in minute ventilation compared with wakefulness. During NREM sleep, the heart rate is regular and slowed and blood pressure is lower than in wakefulness. Cardiac output also falls. During periods of REM sleep, breathing becomes more irregular. Ventilatory responsiveness decreases further. With the loss of muscle tone of the chest wall, which occurs normally in REM, the diaphragm becomes the only active muscle of respiration. This REM-related decreased ventilation may place individuals with obesity or restrictive or obstructive lung diseases at risk for marked hypoxemia in REM. Also during REM sleep, heart rate and blood pressure become more irregular, with higher blood pressures during REM as compared with NREM. Overall, blood pressure is lower during sleep than in wakefulness, and 24-h blood pressure monitoring shows a "dipping pattern."¹² Cerebral blood flow declines during NREM sleep and increases during REM sleep, in association with cerebral metabolism and oxygen consumption.

In patients with SDB, repetitive upper airway obstruction during sleep leads to cyclic decrements in airflow (apneas and hypopneas), which are terminated by cyclic brief arousals that lead to transient resumption of airflow. The apnea-recovery-apnea cycle may occur hundreds of times over the night. Varying levels of cyclic oxygen desaturation are associated with respiratory events, with the oxygen desaturation nadir occurring at the termination of the event.¹³ The severity of oxygen desaturation depends upon the length of the respiratory events, the completeness of airway obstruction (apnea vs hypopnea), the frequency of respiratory events, and the oxygen stores in the lung, which, in turn, depend upon body weight, body position, and the presence or absence of respiratory disorders. In addition, other factors that affect oxygen delivery and consumption are likely to be important. Because of the normal motor atonia of REM sleep, individuals are more at risk for the development of apnea during REM sleep than NREM sleep. Oxygen desaturation also tends to be more prominent in REM sleep.

In association with recurrent apneas, there are cyclic changes in blood pressure, heart rate, and central hemodynamics,¹³ which may have acute effects (Table 2). Blood pressure is lowest at the start of the apnea, increases gradually during the event, and rises markedly at apnea termination coincident with arousal, the nadir of oxygen saturation, and the release of negative intrathoracic pressure and resumption of airflow. The normal dipping pattern of blood pressure during sleep may disappear¹⁴ and be replaced by a pattern such as the one shown in Figure 1. Heart rate decreases during apnea, particularly just before apnea termination, and accelerates with arousal. Pulmonary artery pressure increases with apnea, with the greatest increments during REM sleep in patients with daytime pulmonary hypertension.¹⁵ Reductions in stroke volume and cardiac output, most marked at apnea termination, have been reported in humans,¹⁶ although more recent animal data suggest that stroke volume declines during apnea and returns to normal at apnea termination.¹⁷ Cerebral autoregulation is insufficient to protect the brain from these hemodynamic changes and cerebral perfusion pressure declines, particularly early in apnea when increased intrathoracic pressure is associated with a fall in systemic blood pressure and a rise in central venous pressure with a concomitant increase in intracerebral pressure.^18,19 Continuous positive airway pressure (CPAP) therapy of SDB has been shown to improve many of these transient hemodynamic changes.^14,20

The acute consequences of SDB during the night may include arrhythmias and conduction disturbances, cardiac and cerebral ischemia, and nocturnal pulmonary edema. Tachy-brady arrhythmia is the most common arrhythmia associated with SDB, but sinus pauses, heart block, and ventricular ectopy have all been described.²¹ Owing to an imbalance in oxygen delivery and consumption, acute cardiac and cerebral ischemia may occur in patients with preexisting vascular disease, but this has been less well characterized. Nocturnal pulmonary edema has been described in humans and in animal models of obstructive sleep apnea.²²

Pathophysiologic Mechanisms of Acute Cardiovascular Changes in Apnea

As detailed in a recent review,³ the proposed pathophysiologic mechanisms for the acute cardiovascular changes that accompany the apnea-recovery-apnea cycle include (1) negative intrathoracic pressure, (2) hypoxia, and (3) arousals. Negative intrathoracic pressure resulting from upper airway obstruction is associated with increased left ventricular transmural pressure with resultant increased left ventricular afterload and increased venous return to the right heart, leftward shift of the interventricular septum,²⁰ and resultant decreased preload of the left ventricle. The combination of increased afterload and decreased preload leads to a decrease in stroke volume during apnea and an initial fall in blood pressure. Aortic baroreceptors are activated by the increased transmural intrathoracic aortic pressure, but carotid baroreceptors are inhibited because of the fall in blood pressure related to the decreased cardiac output. Sympathetic nerve activity is initially suppressed because the effect of aortic baroreceptors predominates. As the apnea continues, hypoxia may occur, with or without hypercapnia, and this, in turn, stimulates sympathetic output via peripheral chemoreceptors.^23,24 Sympathetic activity increases peripheral vascular resistance through a-adrenergic receptors in the peripheral vasculature and increases heart rate and cardiac output through cardiac receptors. Thus, as shown in Figure 2, cyclic changes in blood pressure and heart rate mirror the changes in sympathetic tone.²⁵ Arousals also contribute to the sympathetic activation at the termination of the apnea.²⁶

The acute effect of SDB on blood pressure was studied in middle-aged patients participating in the Wisconsin Sleep Cohort Study.²⁷ Predictors of an acute pressor response to respiratory events included, in decreasing order of importance, change in minute ventilation, respiratory event duration, changes in heart rate and oxygen saturation, and arousal. An important finding from this study was that even the "nontraditional" hypopneas (defined as a 50% reduction in the amplitude of the respiratory inductance signal accompanied by a 1 to 3% oxygen desaturation), with or without EEG evidence of arousal, were associated with significant increases in blood pressure at termination of the event. The magnitude of the pressor response was greater for those nontraditional events with arousal than for those without arousal.

Chronic Cardiovascular Disorders Associated With SDB

As a group, patients with SDB have an increased risk of HTN, ischemic heart disease, congestive heart failure, and stroke.²⁸ The converse is also true: namely, patients with these disorders have an increased risk for SDB. Early reports suggested a link between SDB and cardiovascular disease,⁵ and more recent epidemiologic studies have better controlled for multiple risk factors. The SHHS⁶ is the largest prospective cohort study to date, enrolling more than 6,000 participants from existing cohorts of cardiovascular and respiratory disease across the United States. Inclusion criteria included age > 40 years, with increased sampling of snoring individuals between ages 40 and 65 years to maximize the prevalence of SDB in the final population. All minorities were recruited. Exclusion criteria were treatment of SDB with CPAP, tracheostomy, and current home oxygen therapy. Participants completed questionnaires on sleep habits, sleepiness, and quality of life; the parent cohorts provided information on cardiovascular risk factors. All subjects received a home visit, which included a health interview, assessment of medication use, blood pressure measurement, and anthropomorphic measurements. Full, unattended polysomnography was performed, with studies scored at a central location using strict criteria for respiratory disturbances, arousals, and other events. Respiratory events used in the calculation of the AHI included apneas, defined as complete or near-complete cessation of airflow by oronasal thermocouples, and hypopneas, defined as decrease in airflow of > 30% of baseline accompanied by > 4% oxygen desaturation. The initial data were analyzed cross-sectionally, with and without adjusting for multiple potential confounding factors including demographics (age, race, sex), anthropomorphic measures (body mass index, waist-hip ratio, neck circumference), alcohol use, cigarette smoking, HTN (self-reported HTN, use of antihypertensive medications, measured blood pressure), self-reported diabetes, and measured plasma lipid levels, depending on the cardiovascular outcome of interest. Cross-sectional analysis of the SHHS cohort is thus enormously helpful in identifying associations between SDB and cardiovascular disease. Future longitudinal analysis will address SDB as a predictor of cardiovascular outcomes.

Limitations of observational studies such as the SHHS include lack of precision of the measurements used to define variables of interest and multiple sources of bias.¹ Causality cannot be determined in cross-sectional analyses. Odds ratios are subject to error, as unknown confounders cannot be corrected for. Also, odds ratios may be subject to overcorrection, if the confounders controlled for in these studies are really intermediates in the pathway to end-stage disease. For example, if SDB causes HTN and this resultant HTN is the mechanism by which SDB leads to other cardiovascular outcomes, controlling for HTN may obscure a true relationship between SDB and cardiovascular disease. Similarly, if SDB directly leads to central obesity or diabetes, adjustment for these factors may be inappropriate. Long-term prospective studies, intervention studies, and animal models are therefore also needed to sort out possible mechanisms and confounders.

Hypertension

A clear independent association between SDB and HTN was found in the cross-sectional analysis of the SHHS,²⁹ with an increasing prevalence of HTN with increasing AHI, after adjustment for demographics, anthropomorphic measures, alcohol intake, and smoking. The odds ratio for HTN, comparing the highest category of AHI (> 30/h) with the lowest category of AHI (< 1.5/h) was 1.37 (95% confidence interval [CI], 1.03 to 1.83). Associations of HTN with SDB were seen in men and women, in older and younger individuals, in normal-weight and overweight individuals, and across ethnic groups. Similar associations have been found in other cross-sectional studies. In the only prospective study reported to date, the Wisconsin Sleep Cohort Study,³⁰ a dose-response relationship was found between SDB and the presence of HTN 4 years later. Even after adjustment for baseline HTN status, age, sex, anthropomorphic measures, alcohol intake, and smoking, as compared with an AHI reference category of 0/h, the odds of developing HTN at 4 years were increased almost 50% for a baseline AHI of 0.1 to 4.9/h, twofold for an AHI of 5.0 to 14.9, and almost threefold for an AHI of > 15/h. Some, but not all, intervention studies with CPAP have shown that CPAP decreases diurnal HTN.^31,32 The lack of concordance may be due to the fact that not all individuals with SDB have HTN, and CPAP may be most effective in the subgroup of patients who are hypertensive.³³ In one randomized, placebo-controlled, crossover trial of the effects of CPAP on 24-h blood pressure in 68 patients with SDB who were not taking antihypertensive medications,³² CPAP was associated with a small but significant decrease in blood pressure. The fall in diastolic blood pressure was 1.5 mm Hg for the group as a whole and 5.0 mm Hg in patients with 4% desaturation frequencies of > 20/h.

Animal models have provided the most convincing evidence of a causal relationship between SDB and HTN. Experimental SDB produced in a canine model by repeated intermittent airway occlusion over 1 to 3 months was associated with increases in nocturnal and diurnal mean blood pressure, which were reversible after return to normal sleep.³⁴ In a subsequent protocol of sleep fragmentation without airway occlusion, there was a similar increase in nocturnal blood pressure, but an insignificant increase in diurnal blood pressure. Recurrent cycles of chronic intermittent hypoxia in a rodent model were also associated with sustained HTN.³⁵

Coronary Heart Disease

Self-reported coronary heart disease was, at most, modestly associated with SDB in the cross-sectional analysis of the SHHS cohort.³⁶ In the multivariably adjusted model that included demographics, anthropomorphic measures, cigarette smoking, HTN, diabetes, and lipid levels as covariates, the odds ratio of coronary heart disease in the highest quartile of SDB (AHI > 11/h) vs the lowest quartile of SDB (AHI 0 to 1.3/h) was 1.22 (95% CI, 0.93 to 1.59). Based on statististical testing of covariates and concern regarding possible overadjustment for hypertension, a parsimonious model was created, eliminating smoking, body mass index, and all hypertension variables. In the parsimonious model, the odds ratio of coronary heart disease (highest vs lowest quartile) was 1.27 (95% CI, 0.99 to 1.62). No prospective studies have been reported. In a small, uncontrolled series, CPAP has been reported to decrease nocturnal ischemic events in patients with SDB and coexistent ischemic heart disease.³⁷

Congestive Heart Failure

Congestive heart was clearly associated with SDB in the SHHS cohort.³⁶ In the multivariably adjusted model, there was more than a twofold increase in the odds of congestive heart failure in the highest vs the lowest quartile of SDB (odds ratio, 2.22; 95% CI, 1.11 to 4.37), with similar findings in the parsimonious model (odds ratio, 2.38; 95% CI, 1.22 to 4.62). In one small intervention study in individuals with SDB and idiopathic dilated cardiomyopathy, treatment with CPAP was associated with improvement in left ventricular function.³⁸ In a canine model of SDB, 1 to 3 months of SDB was associated with increased left ventricular end-systolic volume and decreased left ventricular ejection fraction on echocardiography.¹⁷

Stroke

Stroke was modestly associated with SDB in the SHHS cohort.³⁶ There was a > 50% increased odds of stroke in the highest vs the lowest quartiles of SDB (odds ratio 1.55, 95% CI 0.96 to 2.50, in the multivariably adjusted model and odds ratio 1.58, 95% CI 1.02 to 2.46, in the parsimonious model). The current evidence for an association between stroke and SDB has recently been reviewed.¹⁹

Pulmonary Hypertension/Cor Pulmonale

While pulmonary hypertension and cor pulmonale were noted in early descriptions of SDB and changes in pulmonary artery pressures are well described acutely, the concept of chronic pulmonary hypertension in SDB is controversial. In one study of 220 patients with SDB, 17% were found to have pulmonary hypertension, generally in the mild to moderate range at rest.³⁹ Pulmonary hypertension was better explained by abnormalities in gas exchange and lung function than SDB. PaCO₂ contributed to 32% of the variance of pulmonary artery mean pressure, FEV₁ to 12%, airway resistance to 4%, and mean nocturnal oxygen saturation to 2%. Right heart structure and function in SDB were examined in 180 participants of the Framingham Heart Study who were also part of the SHHS.⁴⁰ Subjects with SDB who had an RDI > 90th percentile (mean RDI, 42/h) were found to have an increase in right ventricular wall thickness compared with a group of age-, sex-, and nearly BMI-matched subjects who had an RDI < 50th percentile (mean RDI, 5/h). Race, height, HTN, smoking, diabetes, previous myocardial infarction, FEV₁, and left heart echocardiographic covariates were not found to add to the models and were not retained in the analysis. Right atrial dimensions, right ventricular internal dimensions, right ventricular systolic function, and all left ventricular measurements were similar in the two groups. The clinical significance of the finding of an increase in right ventricular wall thickness is unknown. No CPAP intervention studies on right heart structure or function have been reported.

Pathophysiologic Mechanisms Underlying Cardiovascular Disorders in SDB

The increasing evidence linking SDB to cardiovascular diseases raises multiple questions. Is the association causal? What is the direction of the association? Which of the variables are confounders and which are intermediaries? What potential pathophysiologic mechanisms might explain how intermittent nocturnal apnea could lead to chronic diurnal consequences? Ongoing work is being done in multiple areas to define the pathobiology of SDB and understand the potential effects that might lead to chronic cardiovascular disease (Table 3).

Peripheral vascular resistance is regulated by a balance of neural factors, hormonal factors, and local vascular factors. Many of these factors are perturbed in SDB,^41,42 thus potentially contributing to HTN. Of the neural factors studied in SDB, the most consistent finding is sympathetic activation, both acutely, as described above, and chronically. Increased nocturnal and daytime urinary norepinephrine and normetanephrine levels were found in eight patients with SDB, with a subsequent decrease after tracheostomy.⁴³ Daytime muscle sympathetic nerve activity was found to be increased in nine obese patients with SDB as compared with normal-weight or obese control subjects.⁴⁴ Muscle sympathetic nerve activity was also found to increase during a 30-min asphyxic challenge in humans and remain elevated for 20 min after the challenge, after other parameters had returned to normal.⁴⁵ In a rodent model of chronic intermittent hypoxia, the associated sustained daytime HTN was blocked by carotid body denervation or chemical sympathectomy.³⁵ In addition to sympathetic activation, the role of alteration in chemoreceptor or baroreceptor sensitivity in mediating the sustained elevation in blood pressure has also been studied, with conflicting results. However, some investigators have found evidence for tonic activation of peripheral chemoreceptors⁴⁶ and depression of baroreceptor sensitivity.⁴⁷

Circulating factors, such as atrial natriuretic peptide, plasma renin, and aldosterone, which are important in the regulation of circulating blood volume, have been studied in SDB.⁴⁸ Increased release of atrial natriuretic peptide, a hormone with vasodilator and natriuretic properties, has been found in human SDB, while studies of the renin-angiotensin-aldosterone system are conflicting. However, plasma renin activity and blood pressure were elevated in the rodent chronic intermittent hypoxia model, and angiotensin II receptor blockade prevented the development of diurnal HTN.³⁵

Local vascular factors are important for vascular tone as well as vascular remodeling. Circulating endothelin-1, a potent vasoconstrictor with structural effects, was found to be increased during sleep in patients with SDB and decreased after treatment with CPAP.⁴⁹ In contrast, the level of nitric oxide, a local vasodilator, was decreased in patients with untreated SDB and increased with CPAP treatment.⁵⁰ In addition, decreased endothelium-dependent vasodilation, as assessed by infusion of acetylcholine to release nitric oxide, was demonstrated in patients with SDB.⁵¹ Impaired a- and b₂-mediated vascular responses have also been reported in humans with SDB, suggesting a possible functional downregulation of vascular sympathoadrenergic receptors.⁵² Taken together, the evidence suggests that the combination of these neurohumoral factors is sufficient to cause HTN, a major risk factor for other cardiovascular disorders. However, even in the absence of daytime HTN, nocturnal HTN with a nondipping pattern of blood pressure during sleep may predispose to cardiovascular disorders.¹²

In addition to the effects of local factors and shear forces on the vasculature, there is increasing evidence that oxidant injury and inflammation may be important in mediating cardiovascular disease. Repetitive hypoxia may be a form of oxidative stress, leading to the development of reactive oxygen species. Increased neutrophil superoxide generation was found in patients with SDB and treatment with CPAP led to a rapid decrease in superoxide generation.⁵³ Elevated levels of C-reactive protein,⁵⁴ interleukin-6,⁵⁵ and tumor necrosis factor-alpha⁵⁵ have been reported in patients with SDB. Soluble adhesion molecules, which have been implicated in the pathogenesis of atherosclerosis by mediating the adhesion of monocytes to endothelial cells, were found to be elevated in patients with SDB^56,57 and subsequently decreased with CPAP therapy.

Hypercoagulability has been demonstrated in SDB and could contribute to increased cardiovascular morbidity by predisposing to a greater thrombus burden, vascular injury, and atherosclerosis.⁴⁸ Increased fibrinogen⁵⁸ and spontaneous platelet activation and aggregation⁵⁹ have been reported in untreated SDB and also reversed with CPAP therapy. Polycythemia has also been described.

The cross-sectional analysis of the SHHS cohort indicated that SDB is associated with an increased risk of cardiovascular risk factors, including not only HTN, but also diabetes, lipid levels, and obesity as measured by body mass index or waist-hip ratio.⁶⁰ The cluster of vascular risk factors known as the metabolic syndrome or syndrome X, which includes HTN, insulin resistance, hyperlipidemia, and central obesity, may be mediated in part by SDB. Thus, some authors have suggested that syndrome X should include SDB and could be better considered as "syndrome Z."⁶¹ Insulin resistance has been found with increased frequency in patients with SDB as compared with control individuals matched or adjusted for body mass index.^55,62 Increasing AHI was associated with worsening insulin resistance, and the impairment in glucose tolerance was related to the severity of nocturnal oxygen desaturation.⁶² Leptin, an adipocyte hormone important for regulation of body weight and energy expenditure, was found to be increased in patients with SDB.^63,64 CPAP was found to reduce serum leptin levels^63,64 and subcutaneous fat distribution as assessed by abdominal CT.⁶³

Finally, patients with SDB have fragmented sleep and suffer from sleep deprivation. Sleep deprivation itself, without SDB, has been linked to HTN not mediated by muscle sympathetic vasoconstriction⁶⁵ and abnormal glucose tolerance.⁶⁶

Clinical Relevance of SDB and Cardiovascular Abnormalities

The association between SDB and acute and chronic cardiovascular abnormalities has important implications for clinical practice. It is known that SDB is common and that the majority of cases are undiagnosed. From a diagnostic standpoint, the data above indicate that there should be an increased index of suspicion for SDB in individuals with known HTN or other features of the metabolic syndrome, stroke, ischemic heart disease, congestive heart failure, and perhaps pulmonary hypertension. Conversely, in patients with known SDB, cardiovascular disorders should be considered.

From a therapeutic standpoint, these data raise questions about whom to treat, what modality to use for treatment, and what the goals of therapy should be. Few would argue against treatment of SDB in patients who are symptomatic in terms of sleepiness or other neurocognitive dysfunction, as there are clear causal associations between SDB and impairment and clear improvement with treatment such as CPAP.⁶⁷ However, there are patients with SDB who do not have marked symptoms or cardiovascular disease who have severe SDB based on AHI. There are patients with mild-moderate SDB with coexistent cardiovascular disease. There are patients with SDB who have an elevated AHI, but only intermittent or mild oxygen desaturation. A panel of sleep specialists met in 1998, reviewed the available evidence, and published a brief consensus statement on CPAP therapy for SDB.⁶⁷ CPAP therapy was recommended for patients with an RDI of 5/h to 30/h and coexistent neurocognitive symptoms or documented cardiovascular disease including HTN, ischemic heart disease, or stroke. CPAP was also recommended for all patients with an RDI of > 30/h, regardless of symptoms, based on the risk of HTN in this group. Current reports continue to support these recommendations. Elucidating the underlying mechanisms linking SDB to cardiovascular disease, understanding the cut points, if any, at which patients have an increased risk of cardiovascular disease, and evaluating specific therapies in light of the outcomes of cardiovascular disease are essential for determining appropriate therapy for SDB.

Conclusions

SDB is clearly associated with transient nocturnal changes in systemic blood pressure, heart rate, and central hemodynamics. It may be associated with acute nocturnal arrhythmias, cerebral or myocardial ischemia, and pulmonary edema, particularly in patients with preexisting vascular disease. It is increasingly clear that obstructive sleep apnea is associated with chronic systemic HTN, independent of multiple other known risk factors. Good cross-sectional epidemiologic evidence also links SDB to stroke and congestive heart failure, with more modest evidence linking SDB with coronary heart disease and pulmonary hypertension. Pathophysiologic evidence linking nocturnal SDB with chronic cardiovascular disease is increasing. Sympathetic activation, alteration in circulating hormones and local vascular factors, inflammation and oxidant injury, hypercoagulability, metabolic changes such as insulin resistance or leptin resistance, and sleep deprivation are currently under investigation as potential mechanisms underlying chronic cardiovascular disease. The level of SDB that requires treatment in order to prevent cardiovascular consequences is an important clinical question that is, as yet, unanswered.

References

1. Young T, Peppard PE, Gottlieb DJ. Epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002; 165:1217–1239
2. American Academy of Sleep Medicine Task Force. Sleep-related breathing disorders in adults: recommendations for syndrome definition and measurement techniques in clinical research. Sleep 1999; 22:667–689
3. Leung RS, Bradley TD. Sleep apnea and cardiovascular disease. Am J Respir Crit Care Med 2001; 164:2147–2165
4. He J, Kryger MH, Zorick FJ, et al. Mortality and apnea index in obstructive sleep apnea: experience in 385 male patients. Chest 1988; 94:9–14
5. Wright J, Johns R, Watt I, et al. Health effects of obstructive sleep apnoea and the effectiveness of continuous positive airway pressure: a systemic review of the research evidence. BMJ 1997; 314:851–860
6. Quan SF. The Sleep Heart Health Study: design, rationale, and methods. Sleep 1997; 20:645–653
7. Hosselet J, Ayappa I, Norma RG, et al. Classification of sleep-disordered breathing. Am J Respir Crit Care Med 2001; 163:398–405
8. Redline S, Kapur VK, Sanders M, et al. Effects of varying approaches for identifying respiratory disturbances on sleep apnea assessment. Am J Respir Crit Care Med 2000; 161:369–374
9. American Academy of Sleep Medicine Clinical Practice Review Committee. Hypopnea in sleep-disordered breathing in adults. Sleep 2001; 24:469–470
10. Thomas RJ. Definitions of respiratory events in sleep-disordered breathing. Sleep Med 2002; 3:89–91
11. Young T, Palta M, Dempsey J, et al. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993; 328:1230–1235
12. Pickering T, Kario K. Nocturnal non-dipping: what does it augur? Curr Opin Nephrol Hypertens 2001; 10:611–616
13. Shepard JW Jr. Gas exchange and hemodynamics during sleep. Med Clin North Am 1985; 69:1243–1263
14. Akashiba T, Minemura H, Yamamoto H, et al. Nasal continuous positive airway pressure changes blood pressure "non- dippers" to "dippers" in patients with obstructive sleep apnea. Sleep 1999; 22:849–853
15. Niijima M, Kimura H, Edo H, et al. Manifestation of pulmonary hypertension during REM sleep in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1999; 159:1766–1772
16. Garpestad E, Katayama H, Parker JA, et al. Stroke volume and cardiac output decrease at termination of obstructive apneas. J Appl Physiol 1992; 73:1743–1748
17. Parker JD, Brooks D, Kozar LF, et al. Acute and chronic effects of airway obstruction on canine left ventricular performance. Am J Respir Crit Care Med 1999; 160:1888–1896
18. Jennum P, Borgesen SE. Intracranial pressure and obstructive sleep apnea. Chest 1989; 95:279–283
19. Mohsenin V. Sleep-related breathing disorders and risk of stroke. Stroke 2001; 32:1271–1278
20. Shiomi T, Guilleminault C, Stoohs R, et al. Leftward shift of the interventricular septum and pulsus paradoxus in obstructive sleep apnea syndrome. Chest 1991; 100:894–902
21. Guilleminault C, Connolly S, Winkle R. Cardiac arrhythmias and conduction disturbances in 400 patients with sleep apnea syndrome. Am J Cardiol 1983; 52:490–494
22. Fletcher EC, Proctor M, Yu J, et al. Pulmonary edema develops after recurrent obstructive apneas. Am J Respir Crit Care Med 1999; 160:1688–1696
23. Somers VK, Zavala DC, Mark AL, et al. Contrasting effects of hypoxia and hypercapnia on ventilation and sympathetic activity in humans. J Appl Physiol 1989; 67:2101–2106
24. Morgan BJ, Denahan T, Ebert TJ. Neurocirculatory consequences of negative intrathoracic pressure vs. asphyxia during voluntary apnea. J Appl Physiol 1993; 74:2969–2975
25. Hedner J, Hejnell H, Sellgren J, et al. Is high and fluctuating sympathetic activity in the sleep apneoa syndrome of pathogenetic importance for the development of hypertension? J Hypertens 1988; 6:S529–S531
26. Horner RL, Brooks D, Kozar LF, et al. Immediate effects of arousal from sleep on cardiac autonomic outflow in the absence of breathing in dogs. J Appl Physiol 1995; 79:151–162
27. Morgan BJ, Dempsey JA, Pegelow DF, et al. Blood pressure perturbations caused by subclinical sleep-disordered breathing. Sleep 1998; 21:737–746
28. Redline S, Strohl KP. Recognition and consequences of obstructive sleep apnea hypopnea syndrome. Clin Chest Med 1998; 19:1–19
29. Nieto FJ, Young TB, Lind BK, et al. Association of sleep-disordered breathing, sleep apnea, and hypertension in a large community-based study: Sleep Heart Health Study. JAMA 2000; 283:1829–1836
30. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000; 342:1378–1384
31. Worsnop CJ, Pierce RJ, Naughton M. Systemic hypertension and obstructive sleep apnea. Sleep 1993; 16:S148–S149
32. Faccenda JF, Mackay TW, Boon NA, et al. Randomized placebo-controlled trial of continuous positive airway pressure on blood pressure in the sleep apnea-hypopnea syndrome. Am J Respir Crit Care Med 2001; 163:344–348
33. Fletcher EC. Cardiovascular effects of continuous positive airway pressure in obstructive sleep apnea. Sleep 2000; 23(suppl 4):S127–S131
34. Brooks D, Horner RL, Kozar LF, et al. Obstructive sleep apnea as a cause of systemic hypertension: evidence from a canine model. J Clin Invest 1997; 99:106–109
35. Fletcher EC. Invited review: physiological consequences of intermittent hypoxia; systemic blood pressure. J Appl Physiol 2001; 90:1600–1605
36. Shahar E, Whitney CW, Redline S, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001; 163:19–25
37. Peled N, Abinader EG, Pillar G, et al. Nocturnal ischemic events in patients with obstructive sleep apnea syndrome and ischemic heart disease: effects of continuous positive air pressure treatment. J Am Coll Cardiol 1999; 34:1744–1749
38. Malone S, Liu PP, Holloway R, et al. Obstructive sleep apnoea in patients with dilated cardiomyopathy: effects of continuous positive airway pressure. Lancet 1991; 338:1480–1484
39. Chaouat A, Weitzenblum E, Krieger J, et al. Pulmonary hemodynamics in the obstructive sleep apnea syndrome: results in 220 consecutive patients. Chest 1996; 109:380–386
40. Guidry UC, Mendes LA, Evans JC, et al. Echocardiographic features of the right heart in sleep-disordered breathing: the Framingham Heart Study. Am J Respir Crit Care Med 2001; 164:933–938
41. Hedner J. Regulation of systemic vasculature in obstructive sleep apnea syndrome. Sleep 2000; 23(suppl 4):S132–S135
42. Phillips BG, Somers VK. Neural and humoral mechanisms mediating cardiovascular responses to obstructive sleep apnea. Respir Physiol 2000; 119:181–187
43. Fletcher EC, Miller J, Schaaf JW, et al. Urinary catecholamines before and after tracheostomy in patietns with obstructive sleep apnea and hypertension. Sleep 1987; 10:35–44
44. Narkiewicz K, van de Borne PJ, Cooley RL, et al. Sympathetic activity in obese subjects with and without obstructive sleep apnea. Circulation 1998; 98:772–776
45. Morgan BJ, Crabtree DC, Patla M, et al. Combined hypoxia and hycapnia evokes long lasting sympathetic activation in humans. J Appl Physiol 1995; 79:205–213
46. Narkiewicz K, van de Borne PJ, Pesek CA, et al. Selective potentiation of peripheral chemoreflex sensitivity in obstructive sleep apnea. Circulation 1999; 99:1183–1189
47. Carlson JT, Hedner JA, Sellgren J, et al. Depressed baroreflex sensitivity in patients with obstructive sleep apnea. Am J Respir Crit Care Med 1996; 154:1490–1496
48. Eisenssehr I, Noachtar S. Haematological aspects of obstructive sleep apnoea. Sleep Med Rev 2001; 5:207–221
49. Phillips BG, Narkiewicz K, Pesek CA, et al. Effects of obstructive sleep apnea on endothelin-1 and blood pressure. J Hypertens 1999; 17:61–66
50. Ip MS, Lam B, Chan LY, et al. Circulating nitric oxide is suppressed in obstructive sleep apnea and is reversed by nasal continuous positive airway pressure. Am J Respir Crit Care Med 2000; 162:2166–2171
51. Carlson JT, Rangemark C, Hedner JA. Attenuated endothelium-dependent vascular relaxation in patients with sleep apnea. J Hypertens 1996; 14:577–584
52. Grote L, Kraiczi H, Hedner J. Reduced alpha- and beta-2-adrenergic vascular response in patients with obstructive sleep apnea. Am J Respir Crit Care Med 2000; 162:1480–1487
53. Schulz R, Mahmoudi S, Hattar K, et al. Enhanced release of superoxide from polymorphonuclear neutrophils in obstructive sleep apnea: impact of continuous positive airway pressure therapy. Am J Respir Crit Care Med 2000; 162:566–570
54. Shamsuzzaman ASM, Winnicki M, Lanfranchi P, et al. Elevated C-reactive protein in patients with obstructive sleep apnea. Circulation 2002; 105:2462–2464
55. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000; 85:1151–1158
56. Chin K, Nakamura T, Shimizu K, et al. Effects of nasal continuous positive airway pressure on soluble cell adhesion molecules in patients with obstructive sleep apnea syndrome. Am J Med 2000; 109:562–567
57. Dyugovskaya L, Lavie P, Lavie L. Increased adhesion molecules expression and production of reactive oxygen species in leukocytes of sleep apnea patients. Am J Respir Crit Care Med 2002; 165:934–939
58. Chin K, Ohi M, Kita H, et al. Effects of NCPAP therapy on fibrinogen levels in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 1996; 153:1972–1976
59. Bobinsky G, Miller M, Ault K, et al. Spontaneous platelet activation and aggregation during obstructive sleep apnea and its response to therapy with nasal continuous positive airway pressure: a preliminary investigation. Chest 1995; 108:625–630
60. Newman AB, Nieto FJ, Guidry U, et al. Relation of sleep-disordered breathing to cardiovascular disease risk factors: the Sleep Heart Health Study. Am J Epidemiol 2001; 154:50–59
61. Wilcox I, McNamara SG, Collins FL, et al. "Syndrome Z": the interaction of sleep apnoea, vascular risk factors and heart disease. Thorax 1998; 53:25–28
62. Punjabi NM, Sorkin JD, Katzel LI, et al. Sleep-disordered breathing and insulin resistance in middle-aged and overweight men. Am J Respir Crit Care Med 2002; 165:677–682
63. Chin K, Shimizu K, Nakamura T, et al. Changes in intra-abdominal visceral fat and serum leptin levels in patients with obstructive sleep apnea syndrome following nasal continuous positive airway pressure therapy. Circulation 1999; 100:706–712
64. Ip MSM, Lam KSL, Ho C-M, et al. Serum leptin and vascular risk factors in obstructive sleep apnea. Chest 2000; 118:580–586
65. Masahiko K, Phillips BG, Sigurdson G, et al. Effects of sleep deprivation on neural circulatory control. Hypertension 2000; 35:1173–1175
66. Spiegel K, Leproult R, Van Cauter E. Impact of sleep debt on metabolic and endocrine function. Lancet 1999; 354:1435–1439
67. Loube DI, Gay PC, Strohl KP, et al. Indications for positive airway pressure treatment of adult obstructive sleep apnea patients: a consensus statement. Chest 1999; 115:863–866