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Editorial |

Reduced Cardiovascular Morbidity in Obesity-Hypoventilation Syndrome: An Ischemic Preconditioning Protective Effect? FREE TO VIEW

Lena Lavie, PhD; Peretz Lavie, PhD
Author and Funding Information

FINANCIAL/NONFINANCIAL DISCLOSURES: None declared.

The Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel

CORRESPONDENCE TO: Lena Lavie, PhD, The Lloyd Rigler Sleep Apnea Research Laboratory, Unit of Anatomy and Cell Biology, The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, 31096, Haifa, Israel


Copyright 2016, American College of Chest Physicians. All Rights Reserved.


Chest. 2016;150(1):5-6. doi:10.1016/j.chest.2016.02.659
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The resemblance between obese sleepy patients and Joe, the sleepy character in Dickens’s book The Pickwickian Papers was first alluded to in the medical literature toward the end of the 19th century. Monitoring respiration in Pickwickian patients during sleep uncovered repeated apneic episodes causing intermittent hypoxia and sleep fragmentation which led to the description of OSA. Since then, it has been established that despite similar presenting symptoms and patterns of sleep-disordered breathing, some Pickwickian patients also have chronic daytime hypoventilation. These patients are designated as having obesity-hypoventilation syndrome (OHS) that is distinctly different than OSA. OHS is defined by the presence of daytime hypercapnia (PAco2 ≥ 45 mm Hg), sleep-disordered breathing, and obesity (BMI ≥ 30 kg/m2), after exclusion of all other possible causes of chronic hypercapnia. However, the diagnostic criteria of OHS, particularly with respect to the necessity of sleep-disordered breathing and hypercapnia, are still controversial.

FOR RELATED ARTICLE SEE PAGE 68

In comparison with eucapnic obese, OHS is associated with impaired endothelial function and inflammation and a high rate of morbidities and mortality., Because it is well-documented that OSA by itself is also associated with significant endothelial dysfunction, cardiovascular morbidity (CVM), and increased mortality, particularly in relatively younger patients, it could be assumed that OHS patients who also suffer from severe OSA would be at a higher risk of CVM than OHS patients with no or milder forms of OSA.

In this issue of CHEST, Masa et al examine this hypothesis by investigating the association between the severity of OSA and CVM in patients with OHS by performing a cross-sectional analysis of baseline data of 302 patients with OHS participating in a multicenter study that compared the efficacy of three types of OHS treatments. CVM was defined as the presence of any of the following: ischemic cardiomyopathy, chronic heart failure, stroke, pulmonary hypertension, cardiac arrhythmia, and leg arteriopathy. Based on 3% oxygen desaturation index (ODI) tertiles, patients were divided into three OSA severity groups, and the prevalence of a single CVM and groups of CVM were compared between groups.

Surprisingly, the results did not support a worsening effect of OSA on OHS. On the contrary, there was an inverse relationship between the prevalence of CVM and OSA severity. With the exception of ischemic heart disease, the most severe ODI tertile had the lowest prevalence of pulmonary hypertension, stroke, arrhythmia, chronic heart failure, and leg arteriopathy. Of note, chronic heart failure had the strongest inverse relationship with ODI (23.5% vs 8.1%, in the lowest and highest ODI tertiles, respectively) and was the only single variable that reached statistical significance. Patients in the most severe ODI group and the least CVM were younger, predominantly male, more obese, sleepier, and had worse nocturnal and daytime gas exchange. But they had a lower prevalence of hypertension, better exercise tolerance, and fewer hospitalization days than the lowest OSA severity group. Logistic regression analysis performed with three adjustment models revealed significant differences between the most severe and the least severe ODI groups. Adjusting for age and medical treatment did not affect the results. However, significance was lost in all three models once chronic heart failure was removed from the analysis. Similar results were obtained when analysis was repeated using ODI and apnea-hypopnea index as continuous variables.

Even assuming that the pathophysiology of the OHS-related hypoventilation is distinctly different than in the pure OSA, it is difficult to explain why the added burden of severe intermittent hypoxia in OHS was associated with reduced CVM. Of note, the most severe ODI group had a mean ODI of 95.8 and spent 72.7% of total sleep time with an oxygen saturation < 90% and had a mean oxygen saturation of 83.3% compared with 18.2, 58.9%, and 87.7%, respectively, in the least severe group. After excluding the possibility that the results could be accounted for by the younger age of the most severe patients, which could imply early diagnosis and treatment, the authors suggest that the inverse relationship between OSA severity and CVM in OHS might be explained by the protective effect of “ischemic preconditioning.” This adaptive mechanism, in which brief repeated sublethal ischemia and reperfusion episodes confer profound protection from the occurrences of an acute lethal ischemia/reperfusion episode such as in acute myocardial infarction (AMI), was first demonstrated in the cardiovascular system, and then was shown to occur in other organs including skeletal muscles, gut, brain, and the liver. In 2006, Lavie and Lavie hypothesized that the cycles of apneic events in OSA that resemble cycles of ischemia/reperfusion could exert protective effects from more severe ischemic events similar to ischemic preconditioning. Currently, accumulated evidence supports the Lavies’ ischemic preconditioning hypothesis in OSA. For instance, patients with sleep apnea were shown to have age decline mortality rates, and paradoxically increased longevity of elderly patients was documented in comparison with mortality rates in the general population. Additionally, lower postoperative mortality rates and less recurrent CVD events were reported in comparison with those without apnea, suggesting again that OSA may confer some protection against CVM. Moreover, evidence that patients with OSA and total coronary occlusion have more coronary collaterals than patients with similar occlusions but without OSA, and that OSA patients after an AMI have more functional endothelial progenitors cells than patients with AMI without OSA, may provide clues to some of the underlying mechanisms responsible for this protection. The Spanish results should be replicated in a well-planned study, preferably with age-matched groups, before accepting the conclusion that OSA may exert some protective effects in OHS. However, in view of the potentially important clinical implications of the present results regarding treatment and treatment prioritizing in OHS as well as in OSA patients, further research is urgently needed.

References

Lavie P. . Who was the first to use the term Pickwickian in connection with sleepy patients? History of sleep apnoea syndrome. Sleep Med Rev. 2008;12:5-17 [PubMed]journal. [CrossRef] [PubMed]
 
Mokhlesi B. . Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care. 2010;55:1347-1365 [PubMed]journal. [PubMed]
 
Hart N. .Mandal S. .Manuel A. .et al Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax. 2014;69:83-84 [PubMed]journal. [CrossRef] [PubMed]
 
Borel J.C. .Roux-Lombard P. .Tamisier R. .et al Endothelial dysfunction and specific inflammation in obesity hypoventilation syndrome. PLoS One. 2009;4:e6733- [PubMed]journal. [CrossRef] [PubMed]
 
Nowbar S. .Burkart K.M. .Gonzales R. .et al Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med. 2004;116:1-7 [PubMed]journal. [PubMed]
 
Castro-Anon O. .Perez de Llano L.A. .De la Fuente Sanchez S. .et al Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome. PLoS One. 2015;10:e0117808- [PubMed]journal. [CrossRef] [PubMed]
 
Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome.Nat Rev Dis Primers.https://www.researchgate.net/publication/282478127_Obstructive_sleep_apnoea_syndrome. Accessed March 23, 2016.
 
Masa J.F. .Corral J. .Romero A. .et al Protective cardiovascular effect of sleep apnea severity in obesity hypoventilation syndrome. Chest. 2016;150:68-79 [PubMed]journal
 
Murry C.E. .Jennings R.B. .Reimer K.A. . Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136 [PubMed]journal. [CrossRef] [PubMed]
 
Pac-Soo C.K. .Mathew H. .Ma D. . Ischaemic conditioning strategies reduce ischaemia/reperfusion-induced organ injury. Br J Anaesth. 2015;114:204-216 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie L. .Lavie P. . Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses. 2006;66:1069-1073 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie P. .Lavie L. .Herer P. . All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age. Eur Respir J. 2005;25:514-520 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie P. .Lavie L. . Unexpected survival advantage in elderly people with moderate sleep apnoea. J Sleep Res. 2009;18:397-403 [PubMed]journal. [CrossRef] [PubMed]
 
Mokhlesi B. .Hovda M.D. .Vekhter B. .Arora V.M. .Chung F. .Meltzer D.O. . Sleep-disordered breathing and postoperative outcomes after elective surgery: analysis of the nationwide inpatient sample. Chest. 2013;144:903-914 [PubMed]journal. [CrossRef] [PubMed]
 
Steiner S. .Schueller P.O. .Schulze V. .Strauer B.E. . Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion. Chest. 2010;137:516-520 [PubMed]journal. [CrossRef] [PubMed]
 
Berger S. .Aronson D. .Lavie P. .Lavie L. . Endothelial progenitor cells in acute myocardial infarction and sleep-disordered breathing. Am J Respir Crit Care Med. 2013;187:90-98 [PubMed]journal. [CrossRef] [PubMed]
 

Figures

Tables

References

Lavie P. . Who was the first to use the term Pickwickian in connection with sleepy patients? History of sleep apnoea syndrome. Sleep Med Rev. 2008;12:5-17 [PubMed]journal. [CrossRef] [PubMed]
 
Mokhlesi B. . Obesity hypoventilation syndrome: a state-of-the-art review. Respir Care. 2010;55:1347-1365 [PubMed]journal. [PubMed]
 
Hart N. .Mandal S. .Manuel A. .et al Obesity hypoventilation syndrome: does the current definition need revisiting? Thorax. 2014;69:83-84 [PubMed]journal. [CrossRef] [PubMed]
 
Borel J.C. .Roux-Lombard P. .Tamisier R. .et al Endothelial dysfunction and specific inflammation in obesity hypoventilation syndrome. PLoS One. 2009;4:e6733- [PubMed]journal. [CrossRef] [PubMed]
 
Nowbar S. .Burkart K.M. .Gonzales R. .et al Obesity-associated hypoventilation in hospitalized patients: prevalence, effects, and outcome. Am J Med. 2004;116:1-7 [PubMed]journal. [PubMed]
 
Castro-Anon O. .Perez de Llano L.A. .De la Fuente Sanchez S. .et al Obesity-hypoventilation syndrome: increased risk of death over sleep apnea syndrome. PLoS One. 2015;10:e0117808- [PubMed]journal. [CrossRef] [PubMed]
 
Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome.Nat Rev Dis Primers.https://www.researchgate.net/publication/282478127_Obstructive_sleep_apnoea_syndrome. Accessed March 23, 2016.
 
Masa J.F. .Corral J. .Romero A. .et al Protective cardiovascular effect of sleep apnea severity in obesity hypoventilation syndrome. Chest. 2016;150:68-79 [PubMed]journal
 
Murry C.E. .Jennings R.B. .Reimer K.A. . Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74:1124-1136 [PubMed]journal. [CrossRef] [PubMed]
 
Pac-Soo C.K. .Mathew H. .Ma D. . Ischaemic conditioning strategies reduce ischaemia/reperfusion-induced organ injury. Br J Anaesth. 2015;114:204-216 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie L. .Lavie P. . Ischemic preconditioning as a possible explanation for the age decline relative mortality in sleep apnea. Med Hypotheses. 2006;66:1069-1073 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie P. .Lavie L. .Herer P. . All-cause mortality in males with sleep apnoea syndrome: declining mortality rates with age. Eur Respir J. 2005;25:514-520 [PubMed]journal. [CrossRef] [PubMed]
 
Lavie P. .Lavie L. . Unexpected survival advantage in elderly people with moderate sleep apnoea. J Sleep Res. 2009;18:397-403 [PubMed]journal. [CrossRef] [PubMed]
 
Mokhlesi B. .Hovda M.D. .Vekhter B. .Arora V.M. .Chung F. .Meltzer D.O. . Sleep-disordered breathing and postoperative outcomes after elective surgery: analysis of the nationwide inpatient sample. Chest. 2013;144:903-914 [PubMed]journal. [CrossRef] [PubMed]
 
Steiner S. .Schueller P.O. .Schulze V. .Strauer B.E. . Occurrence of coronary collateral vessels in patients with sleep apnea and total coronary occlusion. Chest. 2010;137:516-520 [PubMed]journal. [CrossRef] [PubMed]
 
Berger S. .Aronson D. .Lavie P. .Lavie L. . Endothelial progenitor cells in acute myocardial infarction and sleep-disordered breathing. Am J Respir Crit Care Med. 2013;187:90-98 [PubMed]journal. [CrossRef] [PubMed]
 
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