There are three aspects to sleep apnea: safety, quality of life and cardiovascular risk factor. Sleep apnea can impair quality of life by causing frustration, drop in the performance, impotence and etc. Sleep apnea syndrome (SAS) is a clinical syndrome consisting of a variety of symptoms centered on excessive daily sleepiness. Regardless of the of these symptoms, apnea during sleep itself closely relates to cardiovascular disease and especially obstructive sleep apnea, mediates cardiovascular diseases through multiple mechanisms including hypoxia, increased sympathetic nerve activity derived by arousal and hypoxia, oxidative stress induced during recovery from apnea, and increased cardiac afterload due to negative intra-thoracic pressure. The Sleep Heart Health Study revealed cardiovascular disease increases according to the severity of sleep apnea in a community, and a number of reported high prevalence of sleep apnea in patients with a wide spectrum of cardiovascular disease. Marin et al. reported in his prospective study that incident rate of cardiovascular death and non-fetal cardiovascular events were tripled in patients with untreated severe OSA and CPAP treatment suppressed cardiovascular event rate to nearly the same level as control subjects.¹ Therefore, it is very important to detect severe OSA and treat it in terms of cardiovascular prevention. However, sleep apnea "syndrome" (SAS) is only a tip of iceberg. Young reported that 24 % of male adult had sleep apnea with AHI>5 but only 4 % has symptoms of SAS.² In Japan, Nakayama-Ashida et al.³ screened middle-aged Japanese employees and found only 30 % of the subjects whose RDI was greater than five, had symptom SAS. Considering the high prevalence of sleep apnea in patients with cardiovascular disease, cardiac physicians must always keep in mind the possibility of sleep apnea whenever presented with a patient with cardiovascular disease. Unfortunately, the average cardiologist is not familiar with management of sleep apnea. Thus in 2010, the Japanese Circulation Society published Guidelines for the Management of Sleep Disordered Breathing in Cardiovascular Disease, in collaboration with other major domestic medical societies.⁴ In the Japanese guidelines, it is highly recommended to routinely screen for sleep disordered breathing (SDB) in patients with refractory hypertension and heart failure as well as patients suspected for SAS. For the screening of SDB, a type 3 or 4 monitor device is acceptable, but once SDB is screened, polysomnography (PSG) is recommended for the final diagnosis and evaluation of treatment effect.

For the treatment of OSA, the guidelines recommend lifestyle modification including weight control, adequate exercise, smoking cessation, and cessation of nightcap. For OSA targeted treatment, CPAP is of course recommended as a Class I choice. Once OSA treatment with CPAP begins, sleep physicians strictly recommend full PSG to be performed when the patient is admitted to a hospital for one or two nights. However, it is not practical to perform PSG in patients who have severe OSA. For Japanese governmental health insurance, CPAP can be applied without PSG when AHI is greater than 40 (but not 30) with a handy screening device. In patients with AHI less than 40 with screening device, governmental health insurance is applied for CPAP only when AHI is greater than 20 for PSG. The problem with CPAP is its poor tolerability; many patients drop out during treatment. In such patients oral appliance may be applied. In Japan, oral appliance is approved for patients with SAS with AHI>5. However, major limitations of oral appliance are its modest effect on OSA and lack of clinical evidence.

Japanese guidelines also address the treatment of central sleep apnea (CSA), another type of sleep apnea. CSA is a rare type of SDB in the general population. In patients with heart failure, however, central sleep apnea is not uncommon. Reports roughly estimate two out of three patients with heart failure have SDB. Moreover, half of these patients have central sleep apnea, while the other half has obstructive apnea. CSA occurs as a consequence of heart failure. Since CSA in heart failure shares a common mechanism with Cheyne-Stoke respiration, the weaning and waxing pattern of breathing—which is observed in patients with severe heart failure who are awake—they are often referred to as CSR-CSA (Cheyne-Stokes respiration with Central Sleep Apnea). In patients with heart failure, hyperventilation and subsequent hypocapnea are induced by pulmonary congestion. Once hypercapnea is detected by the chemoreceptor, respiratory drive is decreased in order to normalize carbon dioxide. However, since chemoreceptor sensitivity is elevated in heart failure because of increased sympathetic nerve activity, over-suppression of respiration occurs. Thus, since CSR-CSA comes as a consequence of heart failure, optimal treatment of heart failure could reduce CSR-CSA. Japanese guidelines therefore recommend optimal treatment of heart failure first. However, despite optimization of heart failure treatment, a substantial degree of CSR-CSA often remains. In such patients, measures aimed at the elimination of CSR-CSA should be taken. Several treatment modalities are reported to be effective for CSR-CSA. A randomized study conducted in Japan reported night oxygen inhalation as modestly effective for CSR-CSA and improves symptoms, physical activity and cardiac function in patients with heart failure, though it did not improve survival.⁵ Certain agents such as acetazolamide and theophylline were reported to improve CSA but these drugs are not recommended for heart failure. Positive ventilation, including CPAP, bi-level PAP and ASV, has also been applied to CSR-CSA treatment. CPAP which is the most potent treatment to OSA failed to improve survival in heart failure patients with CSR-CSA,⁶ although post-hoc analysis indicated CPAP could eliminate CSR-CSA to AHI <15 in nearly half of the patients.⁷ We also observed that in HF patients, CSR-CSA was treated substantially to AHI<15 by CPAP in about half of the patients⁸ and in another half, i.e. the non-responders to CPAP, ASV or bi-level PAP could treat CSR-CSA efficiently.^9,8 Especially, ASV which supplies pressure support mimicking to patient's own respiratory pressure configuration on top of EPAP (expiratory positive airway pressure) is extremely effective to CSR-CSA. ASV is also better than CPAP or bi-level PAP in terms of compliance. The Japanese guidelines recommend CPAP for the initial treatment for patients with CSR-CSA because it is not so expensive as ASV or bi-level PAP. However, if CPAP is not effective or tolerable, switching to ASV or bi-level PAP is recommended. If any type of NPPV cannot be tolerated by the patient, night oxygen therapy is recommended because of its excellent acceptability. ASV use is rapidly growing in Japan and many Japanese reports on ASV and heart failure have been published from Japan.^{10, 11, 12, 13} Although ASV is markedly effective to CSR-VSA, Effect of ASV on patient's survival is not fully investigated. At least two randomized trials observing survival benefit in patients with SDB and heart failure are ongoing worldwide. In the meantime, Yoshihisa et al. reported death or hospitalization by heart failure occurred much less frequent in ASV treated patients compared with non-ASV treated patients with heart failure and CSR-CSA.¹¹ Takama also reported fetal cardiovascular events is significantly lower in ASV adherent patients with heart failure and severe CSA.¹² Moreover, Koyama et al. reported that ASV treatment significantly decreased cardiac events in patients with mild or no SDB as well as those with more than moderate SDB.¹³ Haruki et al. reported that short term use of ASV increased left ventricular ejection fraction and stroke volume in wake patients ¹⁴. The acute effect of ASV on the stroke volume seems to be greater in patients with high wedge pressure ¹⁵ Thus ASV acutely improves hemodynamics and cardiac function but these acute effects of ASV may not be thorough in its effect on SDB because these effects are exerted in awake patients. These reports raise the question as to whether ASV improves heart failure regardless of the severity of SDB. By supplying positive intra-thoracic pressure, ASV lessens both preload and afterload of the left ventricle. ASV also attenuates sympathetic activity by stretching the lung. Harada et al. reported that ASV acutely attenuates sympathetic activity by directly measuring muscle sympathetic nerve activity.¹⁶ Chronic effects of ASV on sympathetic nerve activity are also reported.^17,18 Although it may not be easy to verify whether ASV improves heart failure regardless of the severity of heart failure, this can be an interesting target for research and more patients with heart failure may benefit from ASV in the future if this hypothesis is verified.

KEY LEARNING POINTS:

• Obstructive sleep apnea is one of the major cardiovascular risk factor. Therefore severe OSA must be screened and treated.
• Central sleep apnea with Cheyne-Stokes respiration occurs as a consequence of heart failure. Optimization of heart failure treatment should be the first line.
• As specific treatment targeted on CSR-CSA, ASV is most effective and improve cardiac function, functional capacity and quality of life; however, its survival benefit has not yet been verified.

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References

1. Marin JM, Carrizo SJ, Vicente E, Agusti AG. 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;365:1046-53.
2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med 1993;328:1230-5.
3. Nakayama-Ashida Y, Takegami M, Chin K et al. Sleep-disordered breathing in the usual lifestyle setting as detected with home monitoring in a population of working men in Japan. Sleep 2008;31:419-25.
4. Guidelines for Diagnosis and Treatment of Sleep Disordered Breathing in Cardiovascular Disease (JCS 2010). http://www.j-circ.or.jp/guideline/pdf/JCS2010,momomura.h.pdf (in Japanese) .
5. Sasayama S, Izumi T, Matsuzaki M et al. Improvement of Quality of Life With Nocturnal Oxygen Therapy in Heart Failure Patients With Central Sleep Apnea. Circ J 2009;73 :1255-1262.
6. Bradley TD, Logan AG, Kimoff RJ et al: Continuous positive airway pressure for central sleep apnea and heart failure. N Engl J Med 2005;353:2025-33.
7. 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;115:3173-80.
8. Dohi T, Kasai T, Narui K et al. Bi-level positive airway pressure ventilation for treating heart failure with central sleep apnea that is unresponsive to continuous positive airway pressure. Circ J 2008;72:1100-5.
9. Kasai T, Kasagi S, Maeno K et al. Adaptive servo-ventilation in cardiac function and neurohormonal status in patients with heart failure and central sleep apnea nonresponsive to continuous positive airway pressure. JACC Heart Failure 2013;1:58–63.
10. Kasai T, Usui Y, Yoshioka T et al: .Effect of Flow-triggered Adaptive Servo-ventilation Compared with Continuous Positive Airway Pressure in Chronic Heart Failure Patients with Coexisting Obstructive Sleep Apnea and Cheyne-Stokes Respiration. Circ Heart Fail 2010;3:140-8.
11. Yoshihisa A, Shimizu T, Owada T et al. Adaptive servo ventilation improves cardiac dysfunction and prognosis in chronic heart failure patients with Cheyne-Stokes respiration. Int Heart J 2011;52:218-23.
12. Takama N, Kurabayashi M. Effectiveness of adaptive servo-ventilation for treating heart failure regardless of the severity of sleep-disordered breathing. Circ J 2011;75:1164-9.
13. Koyama T, Watanabe H, Igarashi G et al. Short-term prognosis of adaptive servo-ventilation therapy in patients with heart failure. Circ J 2011;75:710-2.
14. Haruki N, Takeuchi M, Kaku K, Yoshitani H et al. Comparison of acute and chronic impact of adaptive servo-ventilation on left chamber geometry and function in patients with chronic heart failure. Eur J Heart Fail 2011;13:1140-6.
15. Yamada S, Sakakibara M, Yokota T et al. Acute hemodynamic effects of adaptive servo-ventilation in patients with heart failure. Circ J 2013;77:1214-20.
16. Harada D, Joho S, Oda Y et al. Short term effect of adaptive servo-ventilation on muscle sympathetic nerve activity in patients with heart failure. Auton Neurosci 2011;161:95-102.
17. Koyama T, Watanabe H, Tamura Y et al. Adaptive servo-ventilation therapy improves cardiac sympathetic nerve activity in patients with heart failure. Eur J Heart Fail 2013;15:902-9.
18. Yoshihisa A, Suzuki S, Miyata M et al. A single night' beneficial effects of adaptive servo-ventilation on cardiac overload, sympathetic nervous activity, and myocardial damage in patients with chronic heart failure and sleep-disordered breathing. Circ J 2012;76:2153-8.

Keywords: Apnea, Cardiovascular Diseases, Sleep Apnea Syndromes, Sleep Apnea, Obstructive

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