Health Consequences of Sleep Apnea


                                             


Quick Facts:
  
- over 25 million Americans have sleep apnea [1]
- 80 to 90% of adults with OSA remain undiagnosed [2,3]
- Severe sleep-disordered breathing is associated with a 3-fold increase in all-cause mortality risk and a 5-fold increase in cardiovascular mortality risk [4].
- OSA triples the risk of risk of incident hypertension over a period of 4 years [5]
- 70-83% of patients with drug-resistant hypertension have OSA [6]
- 70% of patients with Type 2 diabetes have sleep apnea (ASAA)
- SDB is present in 77% of men and 64% of women with a history of stroke, 76% of individuals with congestive heart failure and 60% of patients with metabolic syndrome [7,8,9]
- The rate of motor vehicle accidents is seven times higher in patients with sleep apnea than in the average population [10]



Sleep Apnea: Understanding the Cardiometabolic Vicious Cycle 
Liana Groza, DDS

(this article was first published on March 30, 2015 on the Spokane Regional Sleep Apnea Network)
 




The major consequences of obstructive sleep apnea (OSA) include cardiac rhythm abnormalities; hypertension, which is often resistant to medication; intravascular inflammation, which has been linked to a significantly higher risk of heart attack and stroke; and metabolic disturbances, including insulin resistance. As a result, sleep apnea is often one of the main components in the vicious circle connecting obesity, diabetes, cardiovascular disease and stroke.




Diabetes and Insulin Resistance: Both the Sleep Heart Health Study and the Wisconsin Sleep Cohort Study have found an independent association between insulin resistance/ diabetes and OSA in patients who report excessive daytime sleepiness (Ronksley et al. 2009). While obesity is a major determinant of insulin resistance (IR), OSA has been shown to act as an additional, independent risk factor for IR. Both obese and non-obese subjects with diagnosed sleep apnea show higher insulin resistance - with each additional apnea or hypopnea per sleep hour increasing the fasting insulin level by about 0.5% (Manzella et al, 2002).




Body Weight is difficult to control in the presence of sleep apnea, because OSA triggers a dysregulation in the serum leptin levels (a critical hormone controlling energy expenditure, body weight and fat distribution). A 10% weight gain increases the risk of moderate to severe OSA by a factor of 6 and is associated with a 32% increase in the AHI index (Peppard et al 2000). Effective CPAP treatment tends to restore leptin concentrations and shift the hormonal control of body weight toward a normal balance (Phillips et al, 2000).




Systemic Inflammation: Patients with sleep apnea demonstrate increased concentrations of the inflammatory cytokines TNF-alpha and IL-6, which cause fatigue and insulin resistance (Manzella et al, 2002). Another inflammatory marker that is elevated in patients with OSA is CRP (C-reactive protein), an indicator of future heart attack or stroke risk. In OSA patients, CRP levels have been shown to correlate significantly with the severity of sleep apnea (Shamsuzzaman, et al, 2002).



Hypertension in patients with OSA is due to the repetitive episodes of apnea, hypoxia and arousal during sleep, which maintain the body in a state of constant stress and sympathetic drive activation. In time this leads to a dysfunction in normal regulatory mechanisms, resulting in persistent high sympathetic drive which is present even during normal daytime wakefulness and breathing (Kato et al, 2009). CPAP treatment as well as effective treatment with oral appliances have been shown to reduce OSA-associated hypertension to a similar degree (Van Haesendonck et al, 2015, Wilcox et al, 1993). 30-40% of patients with high blood pressure and a striking 83% of patients (96% of males) with drug-resistant hypertension have been shown to suffer from obstructive sleep apnea (ASAA, Logan et al, 2001). In such cases, where 3 or more anti-hypertensive medications fail to reduce the blood pressure below 140/90, a sleep study should be strongly considered.



Cardiac Arrhythmia: cardiac rhythm abnormalities are common in sleep apnea, including significantly higher rates of bradycardia, sinoatrial block and paroxysmal supraventricular tachycardia (Namtvedt 2011, Roche et al. 2003) . These are due to the OSA-induced hypoxemia, hypercapnia and acidosis, as well as the increase in sympathetic stress response. There is a strong association between atrial fibrillation (AF), which is a risk factor for stroke, and OSA. 32-49% of patients with AF have been shown to have sleep apnea (Gami 2005), which increases the likelihood of AF recurrence following treatment; treatment with CPAP appears to substantially reduce the frequency and post-ablation recurrence of AF (Dimitri et al 2012; Fein et al 2013; Hoyer at al 2010; Matiello et al 2010; Ng et at 2011).



Cardiovascular Disease: severe sleep apnea is associated with a 5-fold increase in the risk of cardiovascular mortality (Young et al 2008). The repeated cycles of intermittent hypoxia, arousal and reoxygenation associated with OSA produce elevated levels of reactive oxygen species, which have been shown to cause systemic inflammation, endothelial damage and an increased expression of adhesion molecules, triggering the formation of atherosclerotic plaque and contributing to hypertension (Hayashi 2003). The chronically high levels of systemic inflammation in OSA patients are a known major risk factor for heart attack and stroke, as inflammation leads to atherosclerotic plaque rupture and thromboembolic events (Mangge et al 2014; Murray at al 2013; Thompson et al 2013).



Stroke: Obstructive sleep apnea more than doubles the risk of stroke in men (NIH 2010). Snoring also shows a high correlation with stroke - in fact the likelihood of a stroke is greater in patients who snore than those who smoke (Spriggs 1990). Patients with moderate to severe OSA have a higher incidence of silent strokes than those with milder or no OSA (Minoguchi 2007; Nishibayashi 2008). Multiple mechanisms are likely implicated, but one of the primary contributors is systemic inflammation - with OSA patients consistently showing elevated levels of TNF-alpha, Interleukin-6, CRP and increased carotid intima-media thickness (Minoguchi et al 2007).



Brain Changes, Neurocognitive Effects and Dementia: Levels of Serum Amyloid A (SAA), which has been linked to the development of atherosclerosis, stroke, diabetes and dementia, are more than doubled in patients with moderate to severe OSA, compared to mild OSA or healthy controls (Svatikova et al. 2003).

OSA is associated with neurocognitive impairment, especially in measures of concentration, short- and long-term memory, executive and motor function. CPAP treatment has been shown to produce significant improvements, especially in memory and executive function. Children with OSA show difficulty with sustained attention and behavior, and the severity of the OSA correlates with measures of verbal ability. Younger patients with sleep apnea also scored lower on IQ tests than patients without OSA (Beebe et al 2003; Cassel et al. 1989; Verstraeten 2007).

In a study of patients with moderate to severe apnea, extensive white matter changes were found, indicating myelin loss or damage in brain areas controlling mood, cognition, cardiovascular regulation and breathing control (Macey 2008 ). Gray matter loss and reduced metabolism were also found in multiple areas, primarily in the right hemisphere, as was a reduced cerebral blood flow while awake (Hajak 1995; Kneisley 1993; Yaouhi 2009). An additional implication of these OSA-related neurological changes is that the presence of untreated sleep apnea in patients with a history of stroke makes recovery more challenging (Ryan 2011).



Pregnancy: Because of physiological and hormonal changes, pregnant women are at higher risk for developing or worsening sleep disordered breathing (Venkata and Venkateshiah 2009). Pregnant women with sleep disordered breathing have more than double the rates of hypertension and pre-eclampsia compared to non-snorers, and significantly higher risk of fetal growth retardation (Franklin et al. 2000). OSA is also associated with an increase in pre-term births (mostly as a results of preeclampsia), lower Apgar scores and birth weights as well as maternal medical complications (Louis et al 2010; Sahin et al 2008).



Conclusion

Sleep Apnea is a complex, many-faceted condition that is affected by and in turn impacts some of the most prevalent chronic morbidities in the developed world - such as diabetes, cardiovascular disease and stroke. Because many of these conditions share common causes and pathophysiological mechanisms, it is often difficult to successfully control them by addressing only one contributing risk at a time. This complex interplay of learned behaviors (an unhealthy diet, poor sleep habits and sedentary lifestyle), the physiological changes they trigger (such as systemic inflammation, insulin resistance, sleep apnea, altered leptin and other hormonal levels, adverse changes in endothelial function and vascular physiology) and the resultant reinforcement of unhealthy behaviors (reduced exercise and increased appetite due to low energy as a consequence of poor sleep and hormonal balance alterations) makes it imperative that patients and their health care teams understand every component of this vicious circle and formulate a comprehensive, specific plan of action to address each root cause simultaneously.




For additional supporting literature and recent studies please see
Physician References


References

Quick Facts:


1. MyApnea.org https://myapnea.org/

2. American Academy of Sleep Medicine
http://www.aasmnet.org/resources/factsheets/sleepapnea.pdf

3. Daulatzai, M A. Death by a thousand cuts in Alzheimer’s disease: hypoxia—the prodrome. Neurotoxicity research. 2013; 24:216-43

4. Young T., Finn L., Peppard P. E., Szklo-Coxe M., Austin D., Nieto F. J., Stubbs R. & Hla K. M. Sleep disordered breathing and mortality: eighteen-year follow-up of the Wisconsin sleep cohort. Sleep. 2008; 31:1071-8.

5. Quan S. F. & Gersh B. J. (2004). Cardiovascular consequences of sleep-disordered breathing: Past, present and future report of a workshop from the national center on sleep disorders research and the national heart, lung, and blood institute. Circulation. 2004; 109:951-7.

6. Pedrosa, R. P., Drager, L. F., Gonzaga, C. C., Sousa, M. G., de Paula, L. K., Amaro, A. C., Amodeo C et al. Obstructive sleep apnea the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011; 58:811-7.

7. Dyken, M. E., Somers, V. K., Yamada, T., Ren, Z. Y., & Zimmerman, M. B. Investigating the relationship between stroke and obstructive sleep apnea. Stroke. 1996; 27:401-7.

8. Oldenburg, O., Lamp, B., Faber, L., Teschler, H., Horstkotte, D. & Töpfer, V. Sleep‐disordered breathing in patients with symptomatic heart failure: A contemporary study of prevalence in and characteristics of 700 patients. European journal of heart failure. 2007; 9:251-7.

9. Drager, L. F., Togeiro, S. M., Polotsky, V. Y., & Lorenzi-Filho, G. Obstructive sleep apnea: a cardiometabolic risk in obesity and the metabolic syndrome. Journal of the American College of Cardiology. 2013; 62:569-76.

10. Teran-Santos, J., A. Jimenez-Gomez, and J. Cordero-Guevara. "The association between sleep apnea and the risk of traffic accidents." New England Journal of Medicine 340.11 (1999): 847-851.






Sleep Apnea: Understanding the Cardiometabolic Vicious Cycle



Weight loss, diabetes and systemic inflammation

Manzella, D., et al. "Soluble leptin receptor and insulin resistance as determinant of sleep apnea." International journal of obesity and related metabolic disorders: journal of the International Association for the Study of Obesity 26.3 (2002): 370-375.

Peppard, Paul E., et al. "Longitudinal study of moderate weight change and sleep-disordered breathing." Jama 284.23 (2000): 3015-3021.

Phillips, Bradley G., et al. "Increases in leptin levels, sympathetic drive, and weight gain in obstructive sleep apnea." American Journal of Physiology-Heart and Circulatory Physiology 279.1 (2000): H234-H237.

Ronksley, Paul E., et al. "Obstructive sleep apnoea is associated with diabetes in sleepy subjects." Thorax 64.10 (2009): 834-839.

Shamsuzzaman, Abu SM, et al. "Elevated C-reactive protein in patients with obstructive sleep apnea." Circulation 105.21 (2002): 2462-2464.



Hypertension and Cardiovascular Disease


Dimitri, Hany, et al. "Atrial remodeling in obstructive sleep apnea: implications for atrial fibrillation." Heart Rhythm 9.3 (2012): 321-327.

Fein, Adam S., et al. "Treatment of obstructive sleep apnea reduces the risk of atrial fibrillation recurrence after catheter ablation." Journal of the American College of Cardiology 62.4 (2013): 300-305.

Gami, Apoor S., et al. "Therapy insight: interactions between atrial fibrillation and obstructive sleep apnea." Nature Clinical Practice Cardiovascular Medicine2.3 (2005): 145-149.

Hoyer, Friedrich Felix, et al. "High prevalence of obstructive sleep apnea in patients with resistant paroxysmal atrial fibrillation after pulmonary vein isolation." Journal of interventional cardiac electrophysiology 29.1 (2010): 37-41.

Kato, Masahiko, et al. "Obstructive sleep apnea and cardiovascular disease."Circulation Journal 73.8 (2009): 1363-1370.

Logan, Alexander G., et al. "High prevalence of unrecognized sleep apnoea in drug-resistant hypertension." Journal of hypertension 19.12 (2001): 2271-2277.

Mangge, Harald, et al. "Antioxidants, inflammation and cardiovascular disease." World journal of cardiology 6.6 (2014): 462.

Matiello, Maria, et al. "Low efficacy of atrial fibrillation ablation in severe obstructive sleep apnoea patients." Europace 12.8 (2010): 1084-1089.

Murray, Katie N., et al. "Systemic immune activation shapes stroke outcome."Molecular and Cellular Neuroscience 53 (2013): 14-25.

Namtvedt, Silje K., et al. "Cardiac arrhythmias in obstructive sleep apnea (from the Akershus Sleep Apnea Project)." The American journal of cardiology 108.8 (2011): 1141-1146.

Ng, Chee Yuan, et al. "Meta-analysis of obstructive sleep apnea as predictor of atrial fibrillation recurrence after catheter ablation." The American journal of cardiology 108.1 (2011): 47-51

Roche, Frederic, et al. "Relationship among the severity of sleep apnea syndrome, cardiac arrhythmias, and autonomic imbalance." Pacing and clinical electrophysiology 26.3 (2003): 669-677.

Thompson, Peter L., S. Mark Nidorf, and John Eikelboom. "Targeting the unstable plaque in acute coronary syndromes." Clinical therapeutics 35.8 (2013): 1099-1107.

Van Haesendonck, G., et al. "Cardiovascular benefits of oral appliance therapy in obstructive sleep apnea: a systematic review." Journal of Dental Sleep Medicine 2.1 (2015): 9-14

Wilcox, I., et al. "Effect of nasal continuous positive airway pressure during sleep on 24-hour blood pressure in obstructive sleep apnea." Sleep 16.6 (1993): 539-544.




Stroke




NIH News April 8, 2010 "Sleep Apnea Tied to Increased Risk of Stroke"
http://www.nih.gov/news/health/apr2010/nhlbi-08.htm

Hayashi, Motonori, et al. "Nocturnal oxygen desaturation correlates with the severity of coronary atherosclerosis in coronary artery disease." CHEST Journal 124.3 (2003): 936-941.

Kadotani, Hiroshi, et al. "Association Between Apolipoprotein E∊ 4 and Sleep-Disordered Breathing in Adults." Jama 285.22 (2001): 2888-2890.

Minoguchi, Kenji, et al. "Silent brain infarction and platelet activation in obstructive sleep apnea." American journal of respiratory and critical care medicine 175.6 (2007): 612-617.

Nishibayashi, Momoka, et al. "Correlation between severity of obstructive sleep apnea and prevalence of silent cerebrovascular lesions." Journal of clinical sleep medicine: JCSM: official publication of the American Academy of Sleep Medicine 4.3 (2008): 242.

Spriggs, David A., et al. "Historical risk factors for stroke: a case control study." Age and ageing 19.5 (1990): 280-287.




Amyloidosis

Svatikova, Anna, et al. "Serum amyloid a in obstructive sleep apnea."Circulation 108.12 (2003): 1451-1454.



Neurologic Consequences

Beebe, Dean W., et al. "The neuropsychological effects of obstructive sleep apnea: a meta-analysis of norm-referenced and case-controlled data." SLEEP-NEW YORK THEN WESTCHESTER- 26.3 (2003): 298-307.

Cassel, W., et al. "[Psychological aspects of sleep related disorders of respiratory control]." Pneumologie (Stuttgart, Germany) 43 (1989): 625-629.

Hajak Goran et al. "Cerebral perfusion during sleep‐disordered breathing."Journal of sleep research 4.s1 (1995): 135-144.

Kneisley, Lawrence W., et al. "Abnormal waking cerebral blood flow in sleep apnea syndrome." Sleep apnea and rhonchpathy. Karger, Basel (1993): 135-139.

Macey, Paul M., et al. "Brain structural changes in obstructive sleep apnea."Sleep 31.7 (2008): 967.

Ryan, Clodagh M., et al. "Influence of continuous positive airway pressure on outcomes of rehabilitation in stroke patients with obstructive sleep apnea."Stroke 42.4 (2011): 1062-1067.

Verstraeten, Edwin. "Neurocognitive effects of obstructive sleep apnea syndrome." Current neurology and neuroscience reports 7.2 (2007): 161-166.

Yaouhi, Khalid, et al. "A combined neuropsychological and brain imaging study of obstructive sleep apnea." Journal of sleep research 18.1 (2009): 36-48.




Maternal and Foetal Health


Franklin, Karl A., et al. "Snoring, pregnancy-induced hypertension, and growth retardation of the fetus." CHEST Journal 117.1 (2000): 137-141.

Louis, Judette M., et al. "Maternal and neonatal morbidities associated with obstructive sleep apnea complicating pregnancy." American journal of obstetrics and gynecology 202.3 (2010): 261-e1.

Sahin, Figen Kir, et al. "Obstructive sleep apnea in pregnancy and fetal outcome." International Journal of Gynecology & Obstetrics 100.2 (2008): 141-146.


Venkata, Chakradhar, and Saiprakash B. Venkateshiah. "Sleep-disordered breathing during pregnancy." The Journal of the American Board of Family Medicine 22.2 (2009): 158-168.