Sleep Medicine 15 (2014) 483–484
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Obstructive sleep apnea research: challenges and new horizons
Badran et al. [1] provide an overview of insights into obstructive sleep apnea (OSA) research with a focus on cardiovascular-specific areas including hypertension, diabetes mellitus, coronary artery disease, stroke and heart failure, and updates of the role of oxidative stress, systemic inflammation and endothelial dysfunction as intermediate pathways. A discussion on the role of experimental animal models to enhance the elucidation of underlying mechanistic pathways is also provided, particularly in terms of isolating the unique effects of specific OSA-related pathophysiologic processes including models of upper airway occlusion and intermittent hypoxia. Undoubtedly our field of sleep medicine has made great strides in our knowledge base in terms of experimental, clinicbased and epidemiologic research. However, there is much need for further investigation not only to inform our understanding of OSA biology, but also to enhance our clinical practice. The animal and human experimental data support the relationships of OSA-related hypoxia [2] and arousals [3] as contributors to sympathetic nervous system activation. It is now well-recognized that not only is OSA associated with hypertension, but also represents an independent predictor of newly diagnosed hypertension in longitudinal studies, particularly in identifying OSA and hypertension relationships most prominent in the non-obese and overall attenuation of the relationship after adjustment for obesity, thereby suggesting the potential role of obesity as an intermediate factor in the pathway [4,5]. Furthermore, the impact of OSA treatment with continuous positive airway pressure (CPAP) and the mandibular advancement device have consistently demonstrated improvements in blood pressure levels and also in non-dipping hemodynamic profiles which has the potential to reduce downstream cardiovascular sequelae such as coronary artery disease and mortality [6]. The findings are perhaps less consistent with OSA in relation to insulin resistance and diabetes mellitus. Although there are clinical and epidemiologic studies which have demonstrated relationships of these entities, the results of OSA interventional trials have not been consistent perhaps due to the limited sample sizes of these studies, suboptimal duration of treatment effect, and a potential lack of focus on specific subgroups that are most likely to derive improvement in metabolic parameters [7]. OSA has also been identified as a risk factor in atherosclerosis, coronary artery disease, and the development of major cardiovascular events [8]. Relationships with OSA and development of stroke in longitudinal investigation have been observed with findings most pronounced in men [9], however, interventional trial data are sparse. Both OSA and central sleep apnea have been implicated in heart failure pathophysiology, and data from large scale multicenter trials are forthcoming regarding the effectiveness of OSA treatment on heart failure outcomes. An area of importance not discussed in this http://dx.doi.org/10.1016/j.sleep.2014.03.004 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
review is that of OSA and cardiac arrhythmias; exciting data have identified a strong magnitude of association of OSA and arrhythmias such as atrial fibrillation [10], however, prospective longitudinal studies are scarce. Moreover, data from intervention studies have uniformly shown a reduction in the recurrence of atrial fibrillation after ablation or cardioversion in the context of treatment of OSA with CPAP versus non-treatment; however, these studies are fraught with limitations including utilizing a retrospective study design and non-randomized nature [11,12]. It is clear that new investigations need to address the limitations of existing data in order for our field to effectively move forward. These include the need for larger scale observational and clinical trial studies such as those performed in the cardiovascular clinical trial world. An example of one of the many ongoing trials is the large-scale DECLARE-TIMI58 trial (clinicaltrials.gov NCT01730534), which is targeted to recruit over twenty thousand participants to examine the effect of a sodium glucose transport protein inhibitor on cardiovascular death, myocardial infarction and ischemic stroke. Moreover, as existing data in OSA has primarily focused on intermediate cardiovascular outcomes, OSA interventional studies should ideally be conducted over a longer period of time in order to capitalize on the ability to identify ‘‘hard’’ clinical outcomes with event rates that are more amenable to capture over a longer duration of follow-up (e.g. 6 year follow up in the DECLARE-TIMI58 trial). Prospective investigation and rigorously performed randomized clinical trial data are also needed to further clarify the impact of OSA treatment in atrial fibrillation recurrence and prevention. Effectively addressing the confounding of obesity by incorporating more sensitive measures of visceral adiposity also represents an opportunity. Of course, overcoming existing limitations is riddled with the challenges of clinical equipoise. However, the notion of randomizing participants to a control arm of a cardiovascular clinical trial in OSA may indeed be reasonable in the face of existing data, which one can argue are preliminarily compelling, but not conclusive due to the inherent limitations previously mentioned. Another challenge is concern about increased participant drop-out rate if a longer intervention duration is considered. The role of novel therapeutics in the treatment of OSA and a personalized approach depending on underlying anatomic and physiologic susceptibilities also represent an exciting avenue of investigation. A conceptual framework of recommended focus on future directions for our field of sleep medicine and circadian rhythm disorders are provided in a recent statement from the joint task force of the Sleep Research Society and American Academy of Sleep Medicine [13]. In particular, the need to leverage a larger multicenter infrastructure is underscored to identify participants for the
484
Editorial / Sleep Medicine 15 (2014) 483–484
large-scale clinical trials that are critical to rigorously and adequately inform our overall understanding and therefore our OSA clinical algorithms in sleep medicine. Moreover, the importance of tailored, personalized medicine is recognized as is the dissemination of data to inform public health policy. In summary, although we have made considerable progress in augmenting our knowledge of the pathophysiology of OSA and its relationships with cardiovascular outcomes through research efforts to date, there remains substantial opportunity to address existing knowledge gaps. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.03.004.
References [1] Badran M, Ayas N, Laher I. Insights into obstructive sleep apnea research. Sleep Med 2014;15(5):485–95. [2] Fletcher EC, Bao G. The rat as a model of chronic recurrent episodic hypoxia and effect upon systemic blood pressure. Sleep 1996;19(10 (Suppl)):S210–2. [3] Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993;103(6 (June)):1763–8. [4] O’Connor GT, Caffo B, Newman AB, et al. Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179(12):1159–64. [5] Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157(15): 1746–52.
[6] Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50(2 (August)):417–23. [7] Nannapaneni S, Ramar K, Surani S. Effect of obstructive sleep apnea on type 2 diabetes mellitus: a comprehensive literature review. World J Diabetes 2013;4(6):238–44. [8] Kasai T, Floras JS, Bradley TD. Sleep apnea and cardiovascular disease: a bidirectional relationship. Circulation 2012;126(12):1495–510. [9] Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea–hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182(2):269–77. [10] Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173(8):910–6. [11] Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107(20):2589–94. [12] Patel D, Mohanty P, Di Biase L, et al. Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure. Circ Arrhythm Electrophysiol 2010;3(5 (October)):445–51. [13] Zee PC, Badr MS, Kushida C, et al. Strategic opportunities in sleep and circadian research: report of the joint task force of the sleep research society and american academy of sleep medicine. Sleep 2014;37(2):219–27.
Reena Mehra Sleep Center, Neurologic Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States Address: Cleveland Clinic Foundation, Sleep Center, Neurologic Institute, 9500 Euclid Avenue Cleveland, OH 44195, United States. Tel.: +1 (216) 444 8777; fax: +1 (216) 636 0090. E-mail address: [email protected] Available online 3 April 2014
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
Obstructive sleep apnea research: challenges and new horizons
Badran et al. [1] provide an overview of insights into obstructive sleep apnea (OSA) research with a focus on cardiovascular-specific areas including hypertension, diabetes mellitus, coronary artery disease, stroke and heart failure, and updates of the role of oxidative stress, systemic inflammation and endothelial dysfunction as intermediate pathways. A discussion on the role of experimental animal models to enhance the elucidation of underlying mechanistic pathways is also provided, particularly in terms of isolating the unique effects of specific OSA-related pathophysiologic processes including models of upper airway occlusion and intermittent hypoxia. Undoubtedly our field of sleep medicine has made great strides in our knowledge base in terms of experimental, clinicbased and epidemiologic research. However, there is much need for further investigation not only to inform our understanding of OSA biology, but also to enhance our clinical practice. The animal and human experimental data support the relationships of OSA-related hypoxia [2] and arousals [3] as contributors to sympathetic nervous system activation. It is now well-recognized that not only is OSA associated with hypertension, but also represents an independent predictor of newly diagnosed hypertension in longitudinal studies, particularly in identifying OSA and hypertension relationships most prominent in the non-obese and overall attenuation of the relationship after adjustment for obesity, thereby suggesting the potential role of obesity as an intermediate factor in the pathway [4,5]. Furthermore, the impact of OSA treatment with continuous positive airway pressure (CPAP) and the mandibular advancement device have consistently demonstrated improvements in blood pressure levels and also in non-dipping hemodynamic profiles which has the potential to reduce downstream cardiovascular sequelae such as coronary artery disease and mortality [6]. The findings are perhaps less consistent with OSA in relation to insulin resistance and diabetes mellitus. Although there are clinical and epidemiologic studies which have demonstrated relationships of these entities, the results of OSA interventional trials have not been consistent perhaps due to the limited sample sizes of these studies, suboptimal duration of treatment effect, and a potential lack of focus on specific subgroups that are most likely to derive improvement in metabolic parameters [7]. OSA has also been identified as a risk factor in atherosclerosis, coronary artery disease, and the development of major cardiovascular events [8]. Relationships with OSA and development of stroke in longitudinal investigation have been observed with findings most pronounced in men [9], however, interventional trial data are sparse. Both OSA and central sleep apnea have been implicated in heart failure pathophysiology, and data from large scale multicenter trials are forthcoming regarding the effectiveness of OSA treatment on heart failure outcomes. An area of importance not discussed in this http://dx.doi.org/10.1016/j.sleep.2014.03.004 1389-9457/Ó 2014 Elsevier B.V. All rights reserved.
review is that of OSA and cardiac arrhythmias; exciting data have identified a strong magnitude of association of OSA and arrhythmias such as atrial fibrillation [10], however, prospective longitudinal studies are scarce. Moreover, data from intervention studies have uniformly shown a reduction in the recurrence of atrial fibrillation after ablation or cardioversion in the context of treatment of OSA with CPAP versus non-treatment; however, these studies are fraught with limitations including utilizing a retrospective study design and non-randomized nature [11,12]. It is clear that new investigations need to address the limitations of existing data in order for our field to effectively move forward. These include the need for larger scale observational and clinical trial studies such as those performed in the cardiovascular clinical trial world. An example of one of the many ongoing trials is the large-scale DECLARE-TIMI58 trial (clinicaltrials.gov NCT01730534), which is targeted to recruit over twenty thousand participants to examine the effect of a sodium glucose transport protein inhibitor on cardiovascular death, myocardial infarction and ischemic stroke. Moreover, as existing data in OSA has primarily focused on intermediate cardiovascular outcomes, OSA interventional studies should ideally be conducted over a longer period of time in order to capitalize on the ability to identify ‘‘hard’’ clinical outcomes with event rates that are more amenable to capture over a longer duration of follow-up (e.g. 6 year follow up in the DECLARE-TIMI58 trial). Prospective investigation and rigorously performed randomized clinical trial data are also needed to further clarify the impact of OSA treatment in atrial fibrillation recurrence and prevention. Effectively addressing the confounding of obesity by incorporating more sensitive measures of visceral adiposity also represents an opportunity. Of course, overcoming existing limitations is riddled with the challenges of clinical equipoise. However, the notion of randomizing participants to a control arm of a cardiovascular clinical trial in OSA may indeed be reasonable in the face of existing data, which one can argue are preliminarily compelling, but not conclusive due to the inherent limitations previously mentioned. Another challenge is concern about increased participant drop-out rate if a longer intervention duration is considered. The role of novel therapeutics in the treatment of OSA and a personalized approach depending on underlying anatomic and physiologic susceptibilities also represent an exciting avenue of investigation. A conceptual framework of recommended focus on future directions for our field of sleep medicine and circadian rhythm disorders are provided in a recent statement from the joint task force of the Sleep Research Society and American Academy of Sleep Medicine [13]. In particular, the need to leverage a larger multicenter infrastructure is underscored to identify participants for the
484
Editorial / Sleep Medicine 15 (2014) 483–484
large-scale clinical trials that are critical to rigorously and adequately inform our overall understanding and therefore our OSA clinical algorithms in sleep medicine. Moreover, the importance of tailored, personalized medicine is recognized as is the dissemination of data to inform public health policy. In summary, although we have made considerable progress in augmenting our knowledge of the pathophysiology of OSA and its relationships with cardiovascular outcomes through research efforts to date, there remains substantial opportunity to address existing knowledge gaps. Conflict of interest The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.03.004.
References [1] Badran M, Ayas N, Laher I. Insights into obstructive sleep apnea research. Sleep Med 2014;15(5):485–95. [2] Fletcher EC, Bao G. The rat as a model of chronic recurrent episodic hypoxia and effect upon systemic blood pressure. Sleep 1996;19(10 (Suppl)):S210–2. [3] Carlson JT, Hedner J, Elam M, Ejnell H, Sellgren J, Wallin BG. Augmented resting sympathetic activity in awake patients with obstructive sleep apnea. Chest 1993;103(6 (June)):1763–8. [4] O’Connor GT, Caffo B, Newman AB, et al. Prospective study of sleep-disordered breathing and hypertension: the Sleep Heart Health Study. Am J Respir Crit Care Med 2009;179(12):1159–64. [5] Young T, Peppard P, Palta M, et al. Population-based study of sleep-disordered breathing as a risk factor for hypertension. Arch Intern Med 1997;157(15): 1746–52.
[6] Bazzano LA, Khan Z, Reynolds K, He J. Effect of nocturnal nasal continuous positive airway pressure on blood pressure in obstructive sleep apnea. Hypertension 2007;50(2 (August)):417–23. [7] Nannapaneni S, Ramar K, Surani S. Effect of obstructive sleep apnea on type 2 diabetes mellitus: a comprehensive literature review. World J Diabetes 2013;4(6):238–44. [8] Kasai T, Floras JS, Bradley TD. Sleep apnea and cardiovascular disease: a bidirectional relationship. Circulation 2012;126(12):1495–510. [9] Redline S, Yenokyan G, Gottlieb DJ, et al. Obstructive sleep apnea–hypopnea and incident stroke: the sleep heart health study. Am J Respir Crit Care Med 2010;182(2):269–77. [10] Mehra R, Benjamin EJ, Shahar E, et al. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med 2006;173(8):910–6. [11] Kanagala R, Murali NS, Friedman PA, et al. Obstructive sleep apnea and the recurrence of atrial fibrillation. Circulation 2003;107(20):2589–94. [12] Patel D, Mohanty P, Di Biase L, et al. Safety and efficacy of pulmonary vein antral isolation in patients with obstructive sleep apnea: the impact of continuous positive airway pressure. Circ Arrhythm Electrophysiol 2010;3(5 (October)):445–51. [13] Zee PC, Badr MS, Kushida C, et al. Strategic opportunities in sleep and circadian research: report of the joint task force of the sleep research society and american academy of sleep medicine. Sleep 2014;37(2):219–27.
Reena Mehra Sleep Center, Neurologic Institute, Cleveland Clinic Lerner College of Medicine of Case Western Reserve University, Cleveland, OH, United States Address: Cleveland Clinic Foundation, Sleep Center, Neurologic Institute, 9500 Euclid Avenue Cleveland, OH 44195, United States. Tel.: +1 (216) 444 8777; fax: +1 (216) 636 0090. E-mail address: [email protected] Available online 3 April 2014
