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Editorial |

Are the Effects of OSA on the Cardiovascular System Reversible? FREE TO VIEW

Geraldo Lorenzi-Filho, MD, PhD; Luciano F. Drager, MD, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

CORRESPONDENCE TO: Geraldo Lorenzi-Filho, MD, PhD, Laboratório do Sono do Instituto do Coração do Hospital das Clinicas da Faculdade de Medicina da USP, Avenida Enéas de Carvalho Aguiar, 44, Oitavo andar, Bloco 1, Sao Paulo 05403-900, Brazil


Copyright 2016, . All Rights Reserved.


Chest. 2016;149(6):1360-1361. doi:10.1016/j.chest.2016.01.005
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OSA may affect as many as 50% of patients with established cardiovascular diseases referred to tertiary cardiology centers. However, OSA remains largely underrecognized in this group of patients in clinical practice. Why is that? One possible explanation is that many nonsleep specialists are not familiarized with OSA diagnosis and treatment. There may also be a perception that the causal link between OSA and cardiovascular diseases remains to be clearly established. Perhaps this is related to the fact that the field lacks large clinical trials showing benefits of OSA treatment on cardiovascular outcomes. On the other hand, it is also possible that sleep specialists have taken for granted that OSA is harmful to the cardiovascular system long before the link was fully established because of the observation that patients with severe OSA experience dramatic episodes of recurrent suffocation during sleep, causing large intrathoracic pressure swings and progressive hypoxia that must putatively harm the cardiovascular system.

FOR RELATED ARTICLE SEE PAGE 1400

In addition, it is well-established that OSA triggers a cascade of deleterious effects to the cardiovascular system, including sympathetic activation, oxidative stress, insulin resistance, endothelial dysfunction, and atherosclerosis. All these intermediate mechanisms may collectively contribute to the risk of coronary artery disease, stroke, and ultimately cardiovascular death. Although the treatment of OSA with CPAP is able to abolish OSA, one important question remains unanswered: can we reverse the effects of OSA on the cardiovascular system when treatment is established? One small randomized trial showed that the treatment of OSA with CPAP is able to return BP values to optimal levels in a significant proportion of patients with prehypertension and masked hypertension. An observational study from Spain showed that the treatment of OSA with CPAP in normotensive patients was able to prevent the development of hypertension. CPAP is also able to ameliorate arterial stiffness as well as markers of diastolic dysfunction in patients with OSA and no other comorbid conditions., Although surrogate cardiovascular outcomes suggest that CPAP therapy can reverse cardiovascular complications of OSA, definitive proof has remained elusive. Reversibility of cardiovascular complications is difficult to answer in humans in which a myriad of confounders such as obesity, hypertension, diabetes, and aging frequently coexist.

Another important challenge to the field is to characterize the relative importance of each primary component of OSA (ie, negative intrathoracic pressure, arousals, and intermittent hypoxia [IH]) to the deleterious effects on the cardiovascular system. Despite these limitations, experimental research allows us to isolate potential confounders and test the effects of specific features of OSA. For example, rodents exposed to IH, mimicking the oxygen profile observed in patients with OSA, develop cardiovascular alterations similar to what is observed in humans. This observation has led to the concept that IH plays a key role in the genesis of cardiovascular disease triggered by OSA and opened the possibility to study the intermediate mechanisms linking OSA to cardiovascular disease., It is surprising, however, that researchers have paid little attention to exploring the reversibility of the cardiovascular and metabolic effects induced by OSA. One previous study found that the impaired glucose homeostasis induced by IH was partially improved with cessation of exposure to IH.

In this issue of CHEST, Castro-Grattoni et al took an important step by evaluating the reversibility of early structural aortic and cardiac remodeling induced by 6 weeks of IH in an animal model. It is striking that all alterations induced by 6 weeks of IH at the aorta, including increased intima-media thickness, mucoid deposition, aortic fibrosis, and elastin fiber disorganization/disruption, were partially or totally reversed after 6 weeks of normoxia. In the heart, perivascular fibrosis was also reversed. These findings reinforce the importance of early recognition and treatment of OSA. However, the present study also raises several questions. The level of IH to which the animals were submitted is only observed in patients with severe OSA. We do not know if less severe IH, which may better mimic what is frequently seen in clinical practice, is also able to promote the cardiovascular alterations observed in the present model. The authors also did not explore the mechanisms leading to cardiovascular remodeling. Because IH causes elevations in BP, the question that remains unanswered is to what extent the effects observed by Castro-Grattoni et al are mediated by alterations in BP. One can always argue that it is much easier and effective to prevent cardiovascular complications by treating high BP than to treat OSA with CPAP. Answers to these and other important questions linking OSA to cardiovascular disease will only be answered using a combination of experimental, translational, and clinical studies.

References

Costa L.E. .Uchôa C.H. .Harmon R.R. .Bortolotto L.A. .Lorenzi-Filho G. .Drager L.F. . Potential underdiagnosis of obstructive sleep apnoea in the cardiology outpatient setting. Heart. 2015;101:1288-1292 [PubMed]journal. [CrossRef] [PubMed]
 
Gottlieb D.J. .Craig S.E. .Lorenzi-Filho G. .et al Sleep Apnea Cardiovascular Clinical Trials-current status and steps forward: the International Collaboration of Sleep Apnea Cardiovascular Trialists. Sleep. 2013;36:975-980 [PubMed]journal. [PubMed]
 
Drager L.F. .Polotsky V.Y. .Lorenzi-Filho G. . Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest. 2011;140:534-542 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Pedrosa R.P. .Diniz P.M. .et al The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension. 2011;57:549-555 [PubMed]journal. [CrossRef] [PubMed]
 
Marin J.M. .Agusti A. .Villar I. .Forner M. .et al Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012;307:2169-2176 [PubMed]journal. [PubMed]
 
Drager L.F. .Bortolotto L.A. .Figueiredo A.C. .Krieger E.M. .Lorenzi G.F. . Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176:706-712 [PubMed]journal. [CrossRef] [PubMed]
 
Arias M.A. .García-Río F. .Alonso-Fernández A. .Mediano O. .Martínez I. .Villamor J. . Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 2005;112:375-383 [PubMed]journal. [CrossRef] [PubMed]
 
Chopra S, Polotsky VY, Jun JC. Sleep apnea research in animals: past, present, and future [published online ahead of print October 8, 2015].Am J Respir Cell Mol Biol.
 
Drager L.F. .Jun J.C. .Polotsky V.Y. . Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab. 2010;24:843-851 [PubMed]journal. [CrossRef] [PubMed]
 
Polak J. .Shimoda L.A. .Drager L.F. .et al Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep. 2013;36:1483-1490 [PubMed]journal. [PubMed]
 
Castro-Grattoni A.L. .Alvarez-Buvé R. .Torres M. .et al Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea. Chest. 2016;149:1400-1408 [PubMed]journal
 
Pépin J.L. .Tamisier R. .Barone-Rochette G. .Launois S.H. .Lévy P. .Baguet J.P. . Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med. 2010;182:954-960 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Polotsky V.Y. .O'Donnell C.P. .Cravo S.L. .Lorenzi-Filho G. .Machado B.H. . Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2015;309:H1101-H1111 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Costa L.E. .Uchôa C.H. .Harmon R.R. .Bortolotto L.A. .Lorenzi-Filho G. .Drager L.F. . Potential underdiagnosis of obstructive sleep apnoea in the cardiology outpatient setting. Heart. 2015;101:1288-1292 [PubMed]journal. [CrossRef] [PubMed]
 
Gottlieb D.J. .Craig S.E. .Lorenzi-Filho G. .et al Sleep Apnea Cardiovascular Clinical Trials-current status and steps forward: the International Collaboration of Sleep Apnea Cardiovascular Trialists. Sleep. 2013;36:975-980 [PubMed]journal. [PubMed]
 
Drager L.F. .Polotsky V.Y. .Lorenzi-Filho G. . Obstructive sleep apnea: an emerging risk factor for atherosclerosis. Chest. 2011;140:534-542 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Pedrosa R.P. .Diniz P.M. .et al The effects of continuous positive airway pressure on prehypertension and masked hypertension in men with severe obstructive sleep apnea. Hypertension. 2011;57:549-555 [PubMed]journal. [CrossRef] [PubMed]
 
Marin J.M. .Agusti A. .Villar I. .Forner M. .et al Association between treated and untreated obstructive sleep apnea and risk of hypertension. JAMA. 2012;307:2169-2176 [PubMed]journal. [PubMed]
 
Drager L.F. .Bortolotto L.A. .Figueiredo A.C. .Krieger E.M. .Lorenzi G.F. . Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med. 2007;176:706-712 [PubMed]journal. [CrossRef] [PubMed]
 
Arias M.A. .García-Río F. .Alonso-Fernández A. .Mediano O. .Martínez I. .Villamor J. . Obstructive sleep apnea syndrome affects left ventricular diastolic function: effects of nasal continuous positive airway pressure in men. Circulation. 2005;112:375-383 [PubMed]journal. [CrossRef] [PubMed]
 
Chopra S, Polotsky VY, Jun JC. Sleep apnea research in animals: past, present, and future [published online ahead of print October 8, 2015].Am J Respir Cell Mol Biol.
 
Drager L.F. .Jun J.C. .Polotsky V.Y. . Metabolic consequences of intermittent hypoxia: relevance to obstructive sleep apnea. Best Pract Res Clin Endocrinol Metab. 2010;24:843-851 [PubMed]journal. [CrossRef] [PubMed]
 
Polak J. .Shimoda L.A. .Drager L.F. .et al Intermittent hypoxia impairs glucose homeostasis in C57BL6/J mice: partial improvement with cessation of the exposure. Sleep. 2013;36:1483-1490 [PubMed]journal. [PubMed]
 
Castro-Grattoni A.L. .Alvarez-Buvé R. .Torres M. .et al Intermittent hypoxia-induced cardiovascular remodeling is reversed by normoxia in a mouse model of sleep apnea. Chest. 2016;149:1400-1408 [PubMed]journal
 
Pépin J.L. .Tamisier R. .Barone-Rochette G. .Launois S.H. .Lévy P. .Baguet J.P. . Comparison of continuous positive airway pressure and valsartan in hypertensive patients with sleep apnea. Am J Respir Crit Care Med. 2010;182:954-960 [PubMed]journal. [CrossRef] [PubMed]
 
Drager L.F. .Polotsky V.Y. .O'Donnell C.P. .Cravo S.L. .Lorenzi-Filho G. .Machado B.H. . Translational approaches to understanding metabolic dysfunction and cardiovascular consequences of obstructive sleep apnea. Am J Physiol Heart Circ Physiol. 2015;309:H1101-H1111 [PubMed]journal. [CrossRef] [PubMed]
 
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