As research continues to grow, sleep apnea’s relationship to other deadly diseases is becoming more clearly defined.
Obstructive sleep apnea (OSA) has become a major issue in the health profile of millions of people. Studies have found connections between OSA and other diseases, and relief from OSA has been shown to improve quality of life. New comorbid conditions that are being linked with OSA include kidney disease, cardiovascular disease, metabolic syndrome, Alzheimer’s disease, obstructive lung disease, asthma, cancer, diabetes mellitus, and pregnancy. However, some of these links between OSA and other diseases have scant evidence and more research is needed before definitive statements can be issued.
Chronic kidney disease (CKD) is a problem that affects approximately 13% of US adults compared to the incidence of OSA, which is found to be about 2% for women and 4% for men1 (some put the overall figure higher, in the range of about 5% to 10% in the general population).2,3 There may be a correlation between OSA and CKD, but the data to prove this are relatively scarce. However, patients with CKD are often hypervolemic due to their low urine output and have a potential fluid shift toward the neck area when sleeping, which can increase upper airway resistance, putting these patients at higher risk for OSA.
CKD has several risk factors in common with OSA including age, smoking, and obesity. In addition, both OSA and CKD share health consequences in that they negatively affect kidney function. These consequences include arterial hypertension, dyslipidemia, metabolic syndrome, and type 2 diabetes mellitus (DM-II). As seen in association with OSA, gender plays a role in developing CKD; males have a higher incidence of both diseases. Based on the data, some researchers have suggested that people who suffer from both CKD and OSA may have a different clinical presentation. Specifically, they may have fewer sleep-related complaints. It also has been suggested that treatment of OSA often changes the course of developing CKD by altering the paths or the effects of other disease processes. OSA treatment using CPAP reduces the incidence of type 2 diabetes mellitus, arterial hypertension, dyslipidemia, and nocturnal hypoxemia—all of which are related to developing CKD or are consequences of CKD.1
Unlike the scarcity of data investigating the correlation between OSA and CKD, the relationship between OSA and cardiovascular disease is becoming well documented. Many cardiac diagnoses have research supporting the notion of OSA as a contributing factor. This link has been established between OSA and hypertension (HTN), left ventricular hypertrophy, coronary artery disease (CAD), atherosclerosis, endothelial dysfunction, vasoconstriction, obesity-related cardiomyopathy, diabetic cardiomyopathy, tachycardia-induced cardiomyopathy, arrhythmias (especially atrial fibrillation), and stroke.2,3 Research also has evaluated the effect of treating OSA with CPAP and studies have shown that many cardiovascular conditions improve (and several improve immediately). The positive impact of CPAP therapy in making improvements in the cardiovascular system has been found in patients with HTN, CAD, heart failure, and both brady- and tachyarrhythmias. A new model is being proposed that there is a bidirectional relationship between OSA and cardiovascular problems. This model proposes that HTN and heart failure stimulate the sympathetic nervous system (SNS), which brings about sodium and fluid retention, which in turn contributes to the nocturnal fluid shift mentioned above while in the supine position. The result of this is an exacerbation of OSA. On the other side of the bidirectional relationship, OSA brings about activation of the SNS during both night and daytime hours, which can cause and/or worsen hypertension. Thus, OSA may be considered as both a cause and a consequence in cardiovascular disease.2
Metabolic syndrome (MS) is a condition that is linked to OSA as well as prediabetes and to cardiovascular issues. Metabolic syndrome is diagnosed if three of five components are present in the patient’s situation. These include:
- an elevated glucose level (also referred to as insulin resistance or hyperglycemia)
- abdominal obesity
- elevated triglycerides
- elevated blood pressure
- reduced high-density lipoprotein (HDL) cholesterol.
Abdominal obesity (also called central obesity) is defined by the distribution of fat at the waist and is determined by measurement of waist circumference or waist-to-hip ratio. For MS to come to full realization, the individual must be susceptible to the metabolic components. This susceptibility is established through a genetic predisposition, lack of physical activity, and use of antipsychotic drugs.4-6 The five components that provide the basis for diagnosing MS are also components in other diagnoses that link closely to OSA, so it is no surprise that MS would be associated with OSA.
Alzheimer’s disease is a neurologic disorder that is characterized by a progressive degeneration of memory, cognitive function, and emotional processes. It is the major cause of dementia in the elderly, and old age is the most important risk factor; however, 90% of those over 65 are free of any signs of dementia. OSA and its recurring episodes of nocturnal hypoxia are implicated in a proposed chain of events that end in an alteration of the brain’s homeostasis and the pathologic changes found in Alzheimer’s disease. This chain of events is one of the models explaining how OSA leads to Alzheimer’s disease. It is thought that repeated bouts of nocturnal hypoxia lead to hypertension, inflammation in the brain, and oxidative stress. These issues lead to vasoconstriction in the brainstem and cortex, resulting in ischemia and cerebral hypoperfusion (impaired glucose metabolism is also brought in at this point as a factor in this cascade of events). The final parts of this simplified chain are amyloid deposits forming in the brain tissue (amyloid plaques), the development of neurofibrillary tangles, and memory and cognitive loss. Note that researchers have found that CPAP therapy in OSA patients has shown a significant impact on improving cognitive function and memory, but there is also evidence that some cognitive deficiencies persist over time despite long-term use of CPAP.7
Chronic Obstructive Pulmonary Disease and Asthma
The distinctions found in the diagnostic realm of obstructive lung disease are sometimes a bit vague and the disease entities can (and often do) overlap. Chronic obstructive pulmonary disease (COPD) and asthma have several common symptoms: cough, wheezing, and shortness of breath (SOB). One other symptom tends to be more exclusive in asthma—that is, feelings of chest tightness. COPD involves two major phenotypes; chronic bronchitis and emphysema. Both emphysema and chronic bronchitis have airway inflammation as part of their underlying conditions. Inflammation is a major component in asthma and is the foundation for the allergic response to irritants and/or allergens. Inflammation in asthma is sometimes classified as eosinophilic or noneosinophilic phenotypes and reflects different inflammatory profiles.8 COPD is more prevalent in the population than asthma, but there is also a group of patients who have both COPD and asthma.
When OSA is linked to patients with COPD and/or asthma, the daytime symptoms are worse. OSA-related nocturnal hypoxemia is more severe in patients with COPD as compared to patients with OSA alone. Asthma symptoms tend to increase at night (more wheezing, coughing, SOB, and chest tightness), which may be caused by OSA or result in increased severity of OSA. OSA tends to establish a condition of permanent inflammation and may be an underlying cause of asthma for non-eosinophilic asthma patients. CPAP therapy improves long-term outcomes for patients with COPD; one study showed a 5-year survival rate of 71% for patients with hypoxemic COPD and moderate-to-severe OSA when using CPAP plus oxygen compared to a 26% survival for similar COPD/OSA patients treated with oxygen alone. In addition, CPAP therapy reduced the number of hospitalizations for acute exacerbations of COPD. CPAP therapy also appears to improve asthma control and reduce daytime and nighttime asthma symptoms but has no effect on changing lung function as measured by FEV1 and bronchial reactivity.9
There are few published studies on the relationship between cancer and OSA to see if there is a link. Research from Spain published in January 2013 examined the association between OSA and cancer and found that there seems to be such a relationship independent of several known confounding factors (including age, sex, body mass index or BMI, smoking status and smoking history, and alcohol intake). Risk of cancer increased based on severity of OSA, but the researchers were impressed by the fact that the time spent with a Spo2 <90% (TSat90) showed stronger predictive value than the apnea-hypopnea index (AHI). The association between OSA and cancer also appears limited to men and to patients less than 65 years of age, but the study recognized that the lack of a connection between cancer and OSA in women and patients >65 years old may be due to a lack of power in the study to detect this connection.10
The association between diabetes mellitus and OSA has been studied extensively, and there is a clear link going both directions. An estimated 8% of adults in the United States have diabetes mellitus and of that number some 90% have type 2. Type 2 diabetes mellitus occurs when the body does not use insulin properly (insulin resistance), which results in hyperglycemia (high blood glucose levels). Studies have shown that in patients with OSA, some 20% to 30% have DM-II and in patients with DM-II some 23% have OSA (regardless of BMI). As mentioned earlier, OSA activates the sympathetic nervous system (as a result of frequent arousals and intermittent hypoxemia) and increases oxidative stress. These changes lead to glycogen breakdown (causing hyperglycemia) and the release of inflammatory mediators, which contributes to insulin resistance.
When examined from the other side, DM-II is thought to cause disturbances in breathing by altering the autonomic nervous system (diabetic neuropathy), thus altering the control of respiration. Treatment of OSA with CPAP has been shown to decrease nighttime glucose levels and decrease the incidence of DM-II in patients with moderate to severe OSA. However, the effect of CPAP therapy on HbA1c (a blood marker used to indirectly monitor blood glucose levels over several weeks) has shown mixed results and is not conclusive. Likewise, the effect of CPAP on improving insulin resistance has shown mixed results.11
There is not a large amount of published research concerning OSA and pregnancy; however, the body of evidence is growing and health care professionals involved with pregnancy should be vigilant in keeping up with new findings. In general, there are differences between the genders concerning OSA. Women don’t have the complaint of snoring or choking as much as men, but women tend to have more daytime somnolence, headaches, and poorer sleep quality. Women also have more apneas related to REM sleep, but have less apnea during non-REM. Screening questionnaires used to assess sleep and possible OSA (such as the Berlin Questionnaire for Sleep) have less predictive value in women compared to men. Pregnancy introduces factors that both contribute to and protect against OSA. Physical changes in the body reflect this: increased weight and elevation of the diaphragm may increase the risk of OSA, but there is a tendency to sleep in a lateral position, and there is less REM sleep in the later stages of pregnancy, both of which reduce the risk. The upper airway narrows late in the pregnancy, which may increase the risk of OSA, but this resolves post-delivery and the risk fades.
Both of the hormones estrogen and progesterone increase throughout pregnancy. Estrogen causes an increase in blood volume (hyperemia), edema of the nasal mucosa, and rhinitis, which would contribute to increased risk of OSA. Progesterone tends to have mixed effects that are related to hyperventilation. With an increased respiratory drive, there may be a more negative inspiratory pressure in the upper airway, which may increase the tendency to collapse. However, the increase in minute ventilation may help protect against airway occlusion. Hypertension during pregnancy (preeclampsia) also may be a factor that increases the risk of OSA, but like the upper airway narrowing, preeclampsia quickly resolves postpartum. Concerning gestational diabetes, OSA may be associated with an increased risk, but there is not yet a sufficient amount of evidence to define this relationship. Fetal compromise and the association with maternal OSA also needs more research; the small number of studies published up through 2012 have shown contradictory results and the study designs have not been utilizing the higher levels of evaluation needed to make quality assessments. Finally, use of CPAP to treat OSA during pregnancy has received little attention and more studies of high-quality design are needed.12
As the evidence in this article points out, OSA crosses over and interacts with several other diseases. OSA often can be both a causative factor for, and a consequence of, other diseases—what researchers term a bidirectional relationship. OSA has been implicated as a player in these other diseases through activation of the sympathetic nervous system, nocturnal cycling of hypoxemia and reoxygenation, frequent arousals, contribution to oxidative stress, and increased and sustained inflammation.13 More research is needed to evaluate these associations and the health implications involved in the pairings, but it is interesting to note that in many circumstances CPAP therapy has stopped or reversed both the OSA and the comorbid condition and the therapy has reduced risk of developing the other disease.
Bill Pruitt, MBA, RRT, CPFT, AE-C, is a senior instructor and director of clinical education in the Department of Cardiorespiratory Sciences, College of Allied Health Sciences, at the University of South Alabama in Mobile, and a PRN therapist at Springhill Medical Center in Mobile. The author has over 30 years’ experience as a respiratory therapist and is involved in state and national issues related to pulmonary health.
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