Sleep Apnea in Cardiology

Updated:Jul 2,2014

Sleep Apnea in Cardiology

Disclosure: Dr. Malhotra has significant research grants from Respironics and Restore Medical; he also has significant Consultant/Advisory Board relationships with Pfizer, Apnex, JMI, Restore Medical, Cephalon, Itamar Medical, and NMT Medical. Dr. Rahangdale and Dr. Yim Yeh have no conflicts.
Pub Date: Monday, July 28, 2008
Author: Shilpa Rahangdale, MD, Atul Malhotra, MD and Susie Yim Yeh, MD

Article Text


Obstructive and central sleep apnea (OSA and CSA) have overlapping but different etiologies and pathophysiologies, but both diseases are prevalent in cardiovascular patients.[1] Both OSA and CSA lead to blood gas derangements and catecholamine surges, which can have deleterious effects on cardiovascular health. OSA is associated with upper airway collapse during sleep [2], generally requiring progressively increasing respiratory effort and subsequent arousal from sleep to resume breathing. Patients with CSA typically have unstable ventilatory control, which can cause wide oscillations in breathing with fluctuating CO2 levels.[3] OSA is more common than CSA, with prevalence estimates suggesting that mild OSA occurs in roughly one of every five adults and moderate OSA in one of every 15 (depending on criteria).[4] These rates, however, are likely an underestimate of today's prevalence, given the pandemic of obesity. Although CSA is less common than OSA, the prevalence of CSA in well-treated congestive heart failure (CHF) populations is high [5], and Cheyne Stokes respiration (CSR, a form of CSA) has been associated with poor outcome.[6] The "Scientific Statement: Sleep Apnea and Cardiovascular Disease" by Somers et al. thoroughly summarizes the available data on the relationship between OSA, CSA, and cardiovascular disease.[7]

OSA causes acute hemodynamic alterations, due to the sustained efforts to breathe during pharyngeal collapse, yielding markedly negative intrathoracic pressure, hypoxemia, and arousal from sleep. Negative intrathoracic pressure increases transmural cardiac pressures, effectively increasing ventricular wall tension and afterload.[8] Additionally, augmented venous return and increased pulmonary arterial pressures, due to hypoxia, may elevate right ventricular pressures resulting in a leftward shift in the intraventricular septum. Concurrently, hypoxemia and arousals cause sympathoexcitation, which increases blood pressure and heart rate.[9] Thus, each obstructive event may be associated with impaired ventricular filling, increased ventricular afterload, and increased myocardial oxygen demand in the hypoxemic patient. Institution of continuous positive airway pressure (CPAP) therapy for sleep apnea decreases transmural cardiac pressures and venous return [10], eliminates hypoxemia and respiratory events, and suppresses catecholamines.[11]

In addition to altered hemodynamics in OSA, both OSA and CSA are associated with intermittent hypoxemia. Repetitive episodes of desaturation, followed by reoxygenation, occur every night in sleep-apnea patients (up to 80-120/hour in severe cases). These repetitive apneas resemble ischemia-reperfusion events, and the reoxygenation phase yields reactive oxygen species.[12] Endothelial cells are especially vulnerable to oxidative stress, due to the central role of nitric oxide (NO) in mediating endothelial cell health. Reactive oxygen species decrease NO production and inactivate what NO may be present, thus reducing the protective effect of endothelium-derived NO.[13] In addition, intermittent hypoxia generates a proinflammatory vascular environment by activating nuclear factor (NF)-kB in endothelial cells, promoting atherosclerosis.[14] The severity of hypoxemia predicts the degree of endothelial dysfunction found in patients with OSA.[15] Though data do not prove causality, OSA patients with marked desaturations apparently have an increased risk of cardiovascular disease.

Somers et al. review mechanisms by which OSA and CSA may cause cardiovascular abnormalities. These mechanisms include intermittent hypoxia, sympathoexcitation, and hemodynamic alterations (see "Scientific Statement: Sleep Apnea and Cardiovascular Disease," Fig. 1). The authors summarize evolving evidence, which strongly suggests that OSA itself contributes to cardiovascular risk. Growing evidence exists that CSA may identify CHF patients with a poor prognosis and, therefore, cannot be considered an epiphenomenon in CHF. However, the authors also note that despite growing numbers of OSA and CSA patients, concomitant with the epidemics of obesity and CHF, respectively, sleep-disordered breathing remains largely undiagnosed and untreated.[16] Given the high prevalence of OSA and CSA, and their probable impact on cardiovascular health, one wonders why so many patients are undiagnosed and if there is justification to pursue these conditions aggressively.

Patient Factors

Lack of Awareness

A lack of awareness regarding sleep apnea may contribute to the burden of undetected disease. The syndrome of OSA is classically defined by both sleep-disordered breathing on polysomnography and symptoms of daytime sleepiness and snoring. Those patients with cardiovascular disease, in particular, CHF and stroke, appear to experience minimal daytime sleepiness with OSA.[17,18] Thus, patients with severe sleep apnea defined by polysomnography may go unrecognized without a high index of suspicion.

However, even the sleepy patient may not seek diagnosis and treatment of OSA for several reasons. First, patients tend to underestimate symptoms or have become accustomed to feeling poorly by altering behaviors such as intake of caffeine. Thus, they may not appreciate their degree of symptomatology. Second, other sequelae of sleep-disordered breathing such as increased cardiovascular risk and neurocognitive dysfunction remain largely unrecognized in the general population. Third, the treatment of OSA (PAP) may be inconvenient and burdensome, discouraging patients from seeking a diagnosis (e.g., the cure may be worse than the disease in their estimation). However, the realization that some patients experience life-changing improvements in symptoms can provide motivation.[19]

If even sleepy patients are reluctant to seek diagnosis and treatment, then how do we convince nonsleepy patients to come forward? After all, compliance with CPAP improves with perceived benefit from therapy (e.g., amelioration in symptoms).[20] Until the cardiovascular risk of asymptomatic OSA patients is better studied and treatment of asymptomatic OSA is proven to improve cardiovascular health, these patients may remain reluctant to seek evaluation. Currently, investigators [21] are conducting the Randomized Intervention with CPAP in CAD patients with Sleep Apnea (RICCADSA) study of CPAP in nonsleepy OSA patients from cardiology clinics. The results of this RICCADSA study may have major clinical implications. Meanwhile, patient education is critical to the management of many chronic diseases, including sleep apnea.

Lack of Acceptance of Diagnostic Techniques

Patient reluctance to undergo overnight diagnostic testing in sleep centers may also contribute to the underdiagnosis of sleep apnea. New changes in Medicare coverage, since the compilation of the "Scientific Statement," now offer the alternative of home testing for some patients. Although home testing for sleep apnea may have limitations based on the type of test ordered, it does offer more information than nocturnal oximetry, which many patients find acceptable.[22] However, patients with coronary artery disease, CHF, and cerebrovascular disease may have central apneas, which may be misdiagnosed using portable equipment. Moreover, the validation of home testing is still emerging for complicated patients, yielding the suggestion that home testing should be reserved for patients without cardiovascular disease. Notably, most patients tolerate in-laboratory polysomnography quite well with only very rare issues of discomfort or inability to sleep.

Lack of Acceptance of Treatment

As stated, patient acceptance is limited by the cumbersome nature of PAP devices. Indeed, early reports suggested that many patients fail to tolerate PAP for >4 hours/night. Newer technologies, including a wider array of better fitting, comfortable masks, heated humidification of the delivered air, and more sophisticated airflow delivery approaches, may increase comfort.[23-25] Patient acceptance may also improve with education about the potential cardiovascular consequences of untreated sleep apnea [26-29], alternatives to PAP therapy, and intensive support during the provision of PAP therapy.[25] In fact, adherence rates to CPAP are comparable to other chronic medical therapies, such as inhalers in asthma or antiepileptic drugs.[30] Non-PAP alternatives, including weight loss, oral appliances, and surgery, should be considered if PAP is untenable, although the data regarding cardiovascular benefits using these alternative strategies for OSA are limited.[31,32]

Clinician Concerns

OSA Cardiovascular Effects Confounded by Associated Comorbidities

Some cardiologists may question the importance of sleep apnea because the association of cardiovascular risk with OSA may be confounded by comorbidities. For instance, OSA may be a marker of obesity and its associated complications. Indeed, early observational trials that demonstrated abnormalities in cardiovascular parameters (blood pressure and other surrogate markers of atherosclerotic risk) in OSA patients did not adequately control for known cardiovascular risk factors such as obesity, hypertension, and smoking status. Somers et al. succinctly review newer, more compelling data that continue to support a link between OSA and hypertension, CHF, stroke, arrhythmias, and myocardial ischemia/infarction after rigorously controlling for known confounding variables.[7] In addition, animal models, cell-culture experiments, and most recently, interventional studies, support the notion that OSA in and of itself has important effects on cardiovascular markers.[13,33-35] Indeed, a causal link between OSA and systemic hypertension is now established.[36]

Lack of Large Randomized Trials Demonstrating Benefit of CPAP

Large, multicenter, randomized, controlled trials demonstrating improved cardiovascular outcomes with CPAP therapy are lacking. The primary limitations in designing such trials have been the uncertain cardiovascular benefits of treating OSA and ethical concerns regarding appropriate controls. An ethical dilemma exists in exposing untreated OSA patients to the risk of daytime symptoms and injury. Previous studies have reported a sevenfold increase in risk of car accidents in OSA patients [37], suggesting that the danger of untreated OSA is not trivial. One option would be to study asymptomatic individuals, but the biology of these patients may be different from clinical OSA syndrome, and asymptomatic patients may be poorly adherent to CPAP therapy.[38] Additionally, an appropriate control for CPAP has been much debated, and even the potential solution of sham-CPAP has possible issues of disrupting sleep and/or being partially effective.[39] Despite these limitations, there is a need for more definitive studies in this field. In addition to the available evidence reviewed in the "Scientific Statement," there exist important biologic reasons, both at the hemodynamic and cellular levels, to believe that intermittent hypoxia and sympathoexcitation associated with OSA can cause independent abnormalities in the cardiovascular system, beyond the risk associated with obesity alone. Valiant efforts are currently underway to randomize large OSA populations (e.g., in China and Australia) to CPAP, assessing hard cardiovascular outcomes. Although the results of this research are years away, these data will be eagerly anticipated.

Until then, there are efforts to target specific populations such as CHF patients. Although randomized controlled studies of CPAP effects on mortality in CHF patients with OSA and CSR are ongoing, studies have shown that CPAP in CHF patients with OSA may improve ejection fraction.[40,41] Somers et al. have also shown that treatment of OSA in patients with atrial fibrillation may prevent recurrence after cardioversion.[42] Although CPAP in stroke patients with OSA remains challenging, due to the increased age and neurocognitive impairment in those afflicted, the recent 10-year study of stroke patients with and without OSA suggests that OSA does increase mortality in this population.[43] Indeed, further research is required, but the observation that certain cardiovascular diseases may benefit if concomitant OSA is treated has potential clinical implications.

Negative Trials for CPAP in CHF

In contrast, although CSA is likely predictive of increased mortality in CHF, the only multicenter, randomized, controlled trial (CANPAP) performed was negative.[44] This finding may reflect inadequate power, since improvements in CHF outcome reduced the expected number of events, or because CPAP is not the ideal therapy for CSA. In fact, an early increase in mortality seen in the CPAP-treated group may have been secondary to the decrease in venous return and worsened cardiac output associated with CPAP in hypovolemic patients.[10] Further analyses of the CANPAP data, however, showed that patients treated with CPAP who achieved an apnea-hypopnea index (AHI) <15 events/hour ("responders") had a mortality benefit.[45] Whether response to CPAP therapy is a marker of a more favorable CHF phenotype, or effective treatment of CSA itself improves mortality, is unclear. In aggregate, there are currently insufficient data to advocate for widespread treatment of CSA in CHF with currently available therapies. However, newer PAP therapies, which stabilize breathing more effectively in CSR, are being studied.[46,47]

In summary, Somers et al. provide an exhaustive review of a topic of burgeoning relevance. The time has come to define the consequences of sleep apnea to include not just symptoms but, also, the effects of accelerated cardiovascular risk. Although further work is required prior to recommending widespread treatment of all sleep apnea patients, the provocative epidemiological, physiological, and clinical data available thus far should presently prompt one to treat symptomatic patients at risk for cardiovascular events. Patient acceptance of the diagnostic and therapeutic process should improve with the adoption of newer technologies, increased patient options in PAP therapy, and careful patient education and follow up. In addition, the increased mortality associated with CSA in CHF may be modifiable if additional novel therapeutic devices and/or drugs are identified. Our hope is that the "Scientific Statement" will energize a collaborative endeavor to improve the care of cardiovascular patients and patients at risk for these conditions.


Dr. Malhotra is funded by National Institute of Health (Bethesda, MD, USA, P50 HL060292, RO1-HL73146, AG024837) and the American Heart Association Established Investigator Award. He has received consulting and research income from Respironics, Inc.




  1. Malhotra A, White DP. Obstructive sleep apnoea. Lancet 2002;360(9328):237-245.
  2. Eckert DJ, Malhotra A. Pathophysiology of adult obstructive sleep apnea. Proc Am Thorac Soc 2008;5(2):144-153.
  3. Eckert DJ, Jordan AS, Merchia P, et al. Central sleep apnea: pathophysiology and treatment. Chest 2007;131(2):595-607.
  4. Young T, Peppard P, Gottlieb D. The epidemiology of obstructive sleep apnea: a population health perspective. Am J Respir Crit Care Med 2002;165:1217-1239.
  5. Macdonald M, Fang J, Pittman SD, et al. The current prevalence of sleep disordered breathing in congestive heart failure patients treated with beta blockers. J Clin Sleep Med 2008;4:38-43.
  6. Lanfranchi PA, Braghiroli A, Bosimini E, et al. Prognostic value of nocturnal Cheyne-Stokes respiration in chronic heart failure. Circulation 1999;99(11):1435-1440.
  7. Somers V, et al. Scientific statement: sleep apnea and cardiovascular disease. Circulation 2008:in press.
  8. Malhotra A, Muse VV, Mark EJ. Case records of the Massachusetts General Hospital. Weekly clinicopathological exercises. Case 12-2003. An 82-year-old man with dyspnea and pulmonary abnormalities. N Engl J Med 2003;348(16):1574-1585.
  9. Caples SM, Gami AS, Somers VK. Obstructive sleep apnea. Ann Intern Med 2005;142(3):187-197.
  10. Magder S. More respect for the CVP. Intensive Care Med 1998;24(7):651-653.
  11. Fessler H, Brower R, Wise R, et al. Mechanism of reduced LV afterload by systolic and diastolic positive pleural pressure. J Appl Physiol 1988;65:1244-1250.
  12. Lavie L. Obstructive sleep apnoea syndrome--an oxidative stress disorder. Sleep Med Rev 2003;7:35-51.
  13. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112(17):2660-2667.
  14. Lorenzi-Filho G, Drager LF. Obstructive sleep apnea and atherosclerosis: a new paradigm. Am J Respir Crit Care Med 2007;175(12):1219-1221.
  15. Punjabi NM, Newman AB, Young TB, et al. Sleep-disordered breathing and cardiovascular disease: an outcome-based definition of hypopneas. Am J Respir Crit Care Med 2008;177(10):1150-1155.
  16. Young T, Evans L, Finn L, et al. Estimation of the clinically diagnosed proportion of sleep apnea syndrome in middle-aged men and women. Sleep 1997;20(9):705-706.
  17. Arzt M, Young T, Finn L, et al. Sleepiness and sleep in patients with both systolic heart failure and obstructive sleep apnea. Arch Intern Med 2006;166(16):1716-1722.
  18. Hsu CY, Vennelle M, Li HY, et al. Sleep-disordered breathing after stroke: a randomised controlled trial of continuous positive airway pressure. J Neurol Neurosurg Psychiatry 2006;77(10):1143-1149.
  19. Patel SR, White DP, Malhotra A, et al. Continuous positive airway pressure therapy for treating sleepiness in a diverse population with obstructive sleep apnea: results of a meta-analysis. Arch Intern Med 2003;163(5):565-571.
  20. McArdle N, Devereux G, Heidarnejad H, et al. Long-term use of CPAP therapy for sleep apnea/hypopnea syndrome. Am J Respir Crit Care Med 1999;159(4 Pt 1):1108-1114.
  21. Peker Y, Glantz H, Thunstrom E, et al. RICCADSA: randomized intervention with CPAP in coronary artery disease and obstructive sleep apnea. Am J Respir Crit Care Med 2008;177:A480.
  22. Pittman SD, Ayas NT, MacDonald MM. Using a wrist-worn device based on peripheral arterial tonometry to diagnose obstructive sleep apnea: in-laboratory and ambulatory validation. Sleep 2004;27(5):923-933.
  23. Kline L, Carlson, P. Humidification improves NCPAP acceptance and use. Am J Respir Crit Care Med 1999;159:A427.
  24. Aloia MS, Stanchina M, Arnedt JT, et al. Treatment adherence and outcomes in flexible vs standard continuous positive airway pressure therapy. Chest 2005;127(6):2085-2093.
  25. Hoy CJ, Vennelle M, Kingshott RN, et al. Can intensive support improve continuous positive airway pressure use in patients with the sleep apnea/hypopnea syndrome? Am J Respir Crit Care Med 1999;159(4 Pt 1):1096-1100.
  26. Marin JM, Carrizo SJ, Vicente E. Long-term cardiovascular outcomes in men with obstructive sleep apnoea-hypopnoea with or without treatment with continuous positive airway pressure: an observational study. Lancet 2005;365(9464):1046-1053.
  27. Yaggi HK, Concato J, Kernan WN. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med 2005;353(19):2034-2041.
  28. Peppard P, Young T, Palta M. Prospective study of the association between sleep disordered breathing and hypertension. N Engl J Med 2000;342:1378-1384.
  29. Lavie P, Here P, Hoffstein V. Obstructive sleep apnea syndrome as a risk factor for hypertension. BMJ 2000;320:479-482.
  30. Kripalani S, Yao X, Haynes RB. Interventions to enhance medication adherence in chronic medical conditions: a systematic review. Arch Intern Med 2007;167(6):540-550.
  31. Gotsopoulos H, Kelly JJ, Cistulli PA. Oral appliance therapy reduces blood pressure in obstructive sleep apnea: a randomized, controlled trial. Sleep 2004;27(5):934-941.
  32. Itzhaki S, Dorchin H, Clark G. The effects of 1-year treatment with a herbst mandibular advancement splint on obstructive sleep apnea, oxidative stress, and endothelial function. Chest 2007;131(3):740-749.
  33. Becker H, Jerrentrup A, Ploch T, et al. Effect of nasal continuous positive airway pressure treatment on blood pressure in patients with obstructive sleep apnea. Circulation 2003;107:68-73.
  34. Pepperell JC, Ramdassingh-Dow S, Crosthwaite N, et al. Ambulatory blood pressure after therapeutic and subtherapeutic nasal continuous positive airway pressure for obstructive sleep apnoea: a randomised parallel trial. Lancet 2002;359(9302):204-210.
  35. Brooks D, Horner RL, Kozar LF, et al. Obstructive sleep apnea as a cause of systemic hypertension. Evidence from a canine model [see comments]. J Clin Invest 1997;99(1):106-109.
  36. Lavie P, Silverberg D, Oksenberg A. Obstructive sleep apnea and hypertension: from correlative to causative relationship. J Clin Hypertens (Greenwich) 2001;3(5):296-301.
  37. Teran-Santos J, Jimenez-Gomez A, Cordero-Guevara J. The association between sleep apnea and the risk of traffic accidents. Cooperative Group Burgos-Santander. N Engl J Med 1999;340(11):847-851.
  38. Barbe F, Mayoralas LR, Duran J. Treatment with continuous positive airway pressure is not effective in patients with sleep apnea but no daytime sleepiness. A randomized, controlled trial. Ann Intern Med 2001;134:1065-1067.
  39. Farre R, Hernandez L, Montserrat JM. Sham continuous positive airway pressure for placebo-controlled studies in sleep apnoea. Lancet 1999;353(9159):1154.
  40. Kaneko Y, Floras J, Usui K, et al. Cardiovascular effects of continuous positive airway pressure in patients with heart failure and obstructive sleep apnea. New Engl J Med. 2003;348:1233-1241.
  41. Mansfield D, Gollogly N, Kaye D et al. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361-366.
  42. Kanagala R, Murali N, Friedman P, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107:2589-2594.
  43. Sahlin C, Sandberg O, Gustafson Y, et al. Obstructive sleep apnea is a risk factor for death in patients with stroke: a 10-year follow-up. Arch Intern Med 2008;168(3):297-301.
  44. Bradley TD, Logan AG, Kimoff RJ, et al. Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353(19):2025-2033.
  45. Arzt M, Floras JS, Logan AG, et al. Suppression of central sleep apnea by continuous positive airway pressure and transplant-free survival in heart failure: a post hoc analysis of the Canadian Continuous Positive Airway Pressure for Patients with Central Sleep Apnea and Heart Failure Trial (CANPAP). Circulation 2007;115(25):3173-3180.
  46. Pittman S, Hill P, Malhotra A, et al. Stabilizing Cheyne Stokes respiration associated with congestive heart failure using computer assisted positive airway pressure. Comput Cardiol 2000;27:201-204.
  47. Teschler H, Dohring J, Wang YM, et al. Adaptive pressure support servo-ventilation: a novel treatment for Cheyne-Stokes respiration in heart failure. Am J Respir Crit Care Med 2001;164(4):614-619.

-- The opinions expressed in this commentary are not necessarily those of the editors or of the American Heart Association

AHA Scientific Journals

AHA Scientific Journals