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Canadian Journal of Cardiology

Sleep Apnea, Intermittent Hypoxemia, and Effects on Ischemic Myocardial Damage: Friend or Foe?

  • Dominik Linz
    Correspondence
    Corresponding author: Dr Dominik Linz, Maastricht Heart and Vascular Center, Maastricht UMC, 6202 AZ Maastricht, The Netherlands. Tel.: +31(0)43-3875093; Mob.: +31(0)6-123-99-182.
    Affiliations
    Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Department of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands

    Centre for Heart Rhythm Disorders, Royal Adelaide Hospital, University of Adelaide, Adelaide, Australia
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  • Benedikt Linz
    Affiliations
    Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
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  • Jordi Heijman
    Affiliations
    Cardiovascular Research Institute Maastricht, Maastricht University, Maastricht, The Netherlands

    Department of Cardiology, Maastricht University Medical Centre, Maastricht, the Netherlands
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Published:February 21, 2020DOI:https://doi.org/10.1016/j.cjca.2020.02.075
      Sleep apnea is strongly associated with coronary artery disease, hypertension, heart failure, atrial fibrillation, and sudden death.
      • McEvoy R.D.
      • Antic N.A.
      • Heeley E.
      • et al.
      CPAP for prevention of cardiovascular events in obstructive sleep apnea.
      • Linz D.
      • McEvoy R.D.
      • Cowie M.R.
      • et al.
      Associations of obstructive sleep apnea with atrial fibrillation and continuous positive airway pressure treatment: a review.
      • Suda S.
      • Kasai T.
      • Matsumoto H.
      • et al.
      Prevalence and clinical correlates of sleep-disordered breathing in patients hospitalized with acute decompensated heart failure.
      • Kadhim K.
      • Middeldorp M.E.
      • Elliott A.D.
      • et al.
      Self-reported daytime sleepiness and sleep-disordered breathing in patients with atrial fibrillation: SNOOZE-AF.
      In the setting of acute myocardial infarction, the presence of sleep apnea is associated with less myocardial salvage and a smaller reduction in infarct size during recovery.
      • Buchner S.
      • Satzl A.
      • Debl K.
      • et al.
      Impact of sleep-disordered breathing on myocardial salvage and infarct size in patients with acute myocardial infarction.
      Several animal models mimicking chronic intermittent hypoxia as one of the key features of sleep apnea have demonstrated an increased infarct size on ischemia-reperfusion injury,
      • Joyeux-Faure M.
      • Stanke-Labesque F.
      • Lefebvre B.
      • et al.
      Chronic intermittent hypoxia increases infarction in the isolated rat heart.
      ,
      • Belaidi E.
      • Joyeux-Faure M.
      • Ribuot C.
      • et al.
      Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea.
      making chronic intermittent hypoxia a prominent modifier of ischemic myocardial damage. Frequent intermittent periods of desaturation followed by reoxygenation lead to the activation of the hypoxia-inducible factor 1 (HIF-1) which acts as a key regulator in the adaptive response to hypoxia
      • Belaidi E.
      • Joyeux-Faure M.
      • Ribuot C.
      • et al.
      Major role for hypoxia inducible factor-1 and the endothelin system in promoting myocardial infarction and hypertension in an animal model of obstructive sleep apnea.
      ,
      • Belaidi E.
      • Thomas A.
      • Bourdier G.
      • et al.
      Endoplasmic reticulum stress as a novel inducer of hypoxia inducible factor-1 activity: its role in the susceptibility to myocardial ischemia-reperfusion induced by chronic intermittent hypoxia.
      and regulates hypoxemia-induced endoplasmic reticulum stresses.
      • Heusch G.
      Molecular basis of cardioprotection: signal transduction in ischemic pre-, post-, and remote conditioning.
      HIF-1 is a heterodimer of the oxygen-sensitive subunit of HIF-1α and HIF-1β. The stability and degradation of HIF-1α proteins is an oxygen-dependent posttranslational process. Whereas under normoxic conditions HIF-1α undergoes proteasomal degradation, under hypoxic conditions HIF-1α stabilizes and colocalizes with HIF-1β in the nucleus, where it binds with hypoxia response elements and drives the transcription of various genes involved in the regulation of both cell survival and cell death.
      In this issue, Moulin et al. investigated the involvement of HIF-1α and the cell stress–induced transcription factor activating transcription factor 4 (ATF4) in chronic intermittent hypoxia-induced cardiomyocyte death after ventricular ischemia-reperfusion injury.
      • Moulin S T.A.
      • Arnaud C.
      • et al.
      Cooperation between HIF-1 and ATF4 in sleep-apnea mediated myocardial injury.
      In wild-type mice, chronic intermittent hypoxia for 21 days resulted in more myocardial damage and larger infarct sizes after ischemia-reperfusion injury. This was associated with HIF-1α up-regulation as well as increased expression of ATF4 and C/EBP homologous binding protein (CHOP), which has been identified as a potential target of ATF4. However, in transgenic mice lacking 1 HIF-1α allele, chronic intermittent hypoxia did not influence infarction size and the increase in CHOP was completely attenuated. Interestingly, ATF4 expression was not affected in this transgenic mouse model, suggesting that chronic intermittent hypoxia and consequent HIF-1α activation may also be responsible for CHOP-dependent cell damage through ATF4-independent pathways. The demonstration that expression of HIF-1α and CHOP, as well as of troponin-T as a marker of myocardial damage, is also increased in human atrial samples from patients with sleep apnea compared with patients without sleep apnea represents an important strength of the study by Moulin et al.
      • Moulin S T.A.
      • Arnaud C.
      • et al.
      Cooperation between HIF-1 and ATF4 in sleep-apnea mediated myocardial injury.
      and suggests that the intermittent hypoxia experiments in mice capture some major components of clinical sleep apnea in humans.
      Moulin et al. provide further evidence for the role of HIF-1 in intermittent hypoxia-associated myocardial damage.
      • Moulin S T.A.
      • Arnaud C.
      • et al.
      Cooperation between HIF-1 and ATF4 in sleep-apnea mediated myocardial injury.
      In addition, their findings give useful insight into the molecular changes mediating the effects of sleep apnea and intermittent hypoxia, which may help to identify new treatment targets in the future. Importantly, sleep apnea differs from several other cardiovascular comorbidities. In contrast to cumulative damage during stable and continuous exposure to pathophysiologic stimuli with comorbidities such as hypertension or obesity, repeated and intermittent exposure to intermittent hypoxia in clinical sleep apnea as well as intermittent hypoxia protocols in sleep apnea animal models may result in dynamic and transient gene or protein expression patterns. The biochemical analyses performed in the study by Moulin et al. provide only a snapshot at a single time point and do not inform about the dynamic biochemical consequences of intermittent hypoxia protocols, which may provide additional information. In addition, hemodynamic and autonomic changes during intermittent hypoxia protocols were not measured but may contribute significantly to intermittent hypoxia-related myocardial damage. Although several sleep apnea rat models incorporate intermittent hypoxia as an important characteristic associated with sleep apnea, ineffective inspiration against the upper airways during obstructive respiratory events in obstructive sleep apnea result in transmural pressure gradients, arousal, and sleep interruption,
      • Bradley T.D.
      • Floras J.S.
      Obstructive sleep apnoea and its cardiovascular consequences.
      which are not simulated in the animal model used here. In addition, the contributions of dynamic biochemical changes, hemodynamic peri- and postapneic responses, and intrathoracic pressure swings and resulting cardiac stretch on top of changes in blood gases to intermittent hypoxia-related damage remain to be further clarified.
      In contrast to the general perception that intermittent hypoxia mainly has detrimental myocardial effects, there is also evidence that intermittent hypoxia might be involved in preconditioning and might therefore even be potentially cardioprotective under certain conditions
      • Shah N.
      • Redline S.
      • Yaggi H.K.
      • et al.
      Obstructive sleep apnea and acute myocardial infarction severity: ischemic preconditioning?.
      ,
      • Ludka O.
      • Stepanova R.
      • Sert-Kuniyoshi F.
      • et al.
      Differential likelihood of NSTEMI vs STEMI in patients with sleep apnea.
      (Fig. 1). A rodent sleep apnea model, which exposed rats to short-term intermittent hypoxia, demonstrated that hypoxia exerted cardioprotective effects in an ischemic-reperfused heart.
      • Beguin P.C.
      • Joyeux-Faure M.
      • Godin-Ribuot D.
      • Levy P.
      • Ribuot C.
      Acute intermittent hypoxia improves rat myocardium tolerance to ischemia.
      Four hours of intermittent hypoxia protocol and a moderate hypoxia load decreased infarction size, whereas 30 minutes of intermittent hypoxia and a high hypoxia load increased infarction size. Moreover, Belaidi et al. provided evidence that the acute preconditioning and cardioprotective effect of intermittent hypoxia in rats is mediated by the interplay between HIF-1 and inducible nitric oxide synthase (iNOS). Inhibition of either HIF-1α or iNOS prevented the previously observed hypoxia-induced preconditioning.
      • Belaidi E.
      • Beguin P.C.
      • Levy P.
      • Ribuot C.
      • Godin-Ribuot D.
      Prevention of HIF-1 activation and iNOS gene targeting by low-dose cadmium results in loss of myocardial hypoxic preconditioning in the rat.
      In agreement, some clinical data show that patients with sleep apnea can have decreased levels of troponin-T after a myocardial infarction and that they are more likely to suffer from non–ST-segment-elevation myocardial infarction than from ST-segment-elevation myocardial infarction compared with individuals without sleep apnea.
      • Shah N.
      • Redline S.
      • Yaggi H.K.
      • et al.
      Obstructive sleep apnea and acute myocardial infarction severity: ischemic preconditioning?.
      ,
      • Ludka O.
      • Stepanova R.
      • Sert-Kuniyoshi F.
      • et al.
      Differential likelihood of NSTEMI vs STEMI in patients with sleep apnea.
      Interestingly, most human studies suggesting a protective effect of sleep apnea on ischemic myocardial damage used a relatively low apnea-hypopnea index (AHI) threshold to identify patients with sleep apnea (AHI > 5/h) and thus included patients with mild to moderate sleep apnea.
      Figure thumbnail gr1
      Figure 1Possible cardioprotective and detrimental myocardial effects during intermittent hypoxia. Ca2+, calcium; CHOP, C/EBP homologous binding protein; HIF1, hypoxia-inducible factor 1; iNOS, inducible nitric oxide synthase; SpO2, oxygen saturation.
      Whether intermittent hypoxia in an individual patient is protective or detrimental is difficult to predict but may have important implications for treatment initiation and for a disease- and outcome-orientated assessment of sleep apnea. Preclinical studies suggest that depending on the duration, depth, and pattern of the hypoxic stimulus, HIF-1 activation can induce either beneficial or detrimental effects. The AHI, which is frequently used to assess sleep apnea severity, counts the number of hypopneas and apneas per hour of sleep but does not represent the absolute degree and duration of oxygen desaturation. Therefore, patients who have frequent short episodes of apnea or hypopnea with minimal desaturations cannot be differentiated from those who have the same number of much longer episodes associated with more pronounced oxygen desaturation.
      • Linz D.
      • Baumert M.
      • Catcheside P.
      • et al.
      Assessment and interpretation of sleep disordered breathing severity in cardiology: clinical implications and perspectives.
      Several studies show that nocturnal hypoxemic burden, reflecting the time spent below 90% oxygen saturation, is a robust and AHI-independent predictor of all-cause and cardiovascular mortality.
      • Baumert M.
      • Immanuel S.A.
      • Stone K.L.
      • et al.
      Composition of nocturnal hypoxaemic burden and its prognostic value for cardiovascular mortality in older community-dwelling men.
      Importantly, nocturnal hypoxemic burden is not exclusively the consequence of oxygen desaturations associated with respiratory events. Hypoxemic burden may also reflect nonspecific drifts in oxygen saturation. Time below 90% oxygen saturation due to frank desaturation as well as due to nonspecific drifts in oxygen saturation contribute to the risk of cardiovascular death.
      • Baumert M.
      • Immanuel S.A.
      • Stone K.L.
      • et al.
      Composition of nocturnal hypoxaemic burden and its prognostic value for cardiovascular mortality in older community-dwelling men.
      A more detailed characterization of the composition of hypoxemic burden may be helpful to assess intermittent hypoxia-related detrimental or protective consequences.
      In addition to the description of intermittent hypoxia during a single night, the biological consequences of sleep apnea may also depend on how long sleep apnea has already been present in an individual patient. Moreover, sleep apnea exhibits a significant night-to-night variability in sleep apnea severity.
      • Linz D.
      • Brooks A.G.
      • Elliott A.D.
      • et al.
      Variability of sleep apnea severity and risk of atrial fibrillation: the VARIOSA-AF study.
      Whether different sleep apnea patterns (paroxysmal vs persistent sleep apnea pattern) display different effects on the heart is unclear and cannot be assessed with a single overnight sleep study, such as is currently used to assess sleep apnea severity. To distinguish new-onset intermittent hypoxia from chronic intermittent hypoxia, and to characterize variability in sleep apnea patterns, a longitudinal assessment or specific biomarkers would be required.
      • Linz D.
      • Baumert M.
      • Desteghe L.
      • et al.
      Nightly sleep apnea severity in patients with atrial fibrillation: potential applications of long-term sleep apnea monitoring.
      The best way to predict the biological consequences of intermittent hypoxia and to assess sleep apnea severity in clinical practice remains unknown.
      • Linz D.
      • Baumert M.
      • Catcheside P.
      • et al.
      Assessment and interpretation of sleep disordered breathing severity in cardiology: clinical implications and perspectives.
      However, the current sleep apnea assessment used in the clinic, which is mainly based on the AHI, appears to be overly simplistic and does not incorporate important components of sleep apnea, such as the composition of intermittent hypoxia and night-to-night variability, which likely modulate the biological consequences of sleep apnea. Assessment of overnight hypoxemic burden by advanced analysis of overnight oximetry and long-term oximetry recordings
      • Linz D.
      • Kadhim K.
      • Brooks A.G.
      • et al.
      Diagnostic accuracy of overnight oximetry for the diagnosis of sleep-disordered breathing in atrial fibrillation patients.
      is becoming feasible and may also facilitate monitoring night-to-night variability of hypoxemic burden.
      • Linz D.
      • Baumert M.
      • Desteghe L.
      • et al.
      Nightly sleep apnea severity in patients with atrial fibrillation: potential applications of long-term sleep apnea monitoring.
      In addition, future studies are warranted to elucidate the preconditioning and cardioprotective properties of sleep apnea in patients and to test whether the CHOP-dependent pathways implicated by Moulin et al.
      • Moulin S T.A.
      • Arnaud C.
      • et al.
      Cooperation between HIF-1 and ATF4 in sleep-apnea mediated myocardial injury.
      represent treatment targets to prevent sleep apnea–related cardiac damage while maintaining iNOS-mediated cardioprotective effects during HIF-1α activation.

      Funding Sources

      The authors have no funding sources to declare.

      Disclosures

      The authors have no conflicts of interest to disclose.

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