Sleep Medicine 14 (2013) 1231–1232
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
The effect of continuous positive airway pressure therapy on vascular function in obstructive sleep apnea: how much is enough? Over the last two decades, obstructive sleep apnea (OSA) has emerged as a considerable public health burden. Due to the ongoing epidemic of obesity, which is strongly linked to OSA, the prevalence of the disease has been steadily rising. According to recent data from the Wisconsin Sleep Cohort, the combination of sleepdisordered breathing as indicated by an apnea–hypopnea index of >5 events per hour and excessive daytime sleepiness occurs in approximately 14% of men and 5% of women between the ages of 30 and 70 years [1]. Cardiovascular diseases (CVDs) represent the principal morbidity and mortality in OSA and large-scale epidemiologic studies have demonstrated an independent relationship between OSA and various cardiac disorders, such as systemic arterial hypertension, ischemic heart disease, heart failure, and stroke [2]. OSA comprises various pathophysiologic triggers for CVD processes including, in particular, intermittent hypoxia (IH) but also sleep fragmentation, intrathoracic pressure swings, and recurrent hypercapnia. These processes in turn have been linked to sympathetic nervous system activity, systemic inflammation, oxidative stress, and possibly metabolic dysfunction as the major pathways in the initiation and progression of CVDs in OSA [3]. Importantly, OSA has been associated with subclinical early alterations in vascular function such as arterial stiffness and endothelial dysfunction. Identification of these early markers of atherosclerosis may be critical, as therapeutic intervention at this stage may prevent the occurrence of major cardiovascular events such as myocardial infarction or stroke. Hence the determination of the efficacy of continuous positive airway pressure (CPAP) therapy in these processes in OSA is of major importance. In this issue of Sleep Medicine, Jones et al. [4] investigate the impact of CPAP therapy on vascular stiffness and endothelial dysfunction in OSA patients without overt CVD using a randomized crossover design. Various evaluation procedures are used in this study, including measurement of augmentation index by pulse wave analysis (PWA) and change with salbutamol or glyceryl trinitrate, pulse wave velocity analysis, and measurement of aortic distensibility by magnetic resonance imaging. The main finding of the study was a trend toward reduced augmentation index with CPAP therapy; however, there was no effect of CPAP therapy on endothelial function, aortic distensibility, and pulse wave velocity. The efficacy of CPAP therapy on arterial stiffness has recently been the subject of two meta-analyses, with both reporting a remarkably concordant improvement with CPAP therapy [5,6]. Two randomized controlled trials of 1 month and 4 months’ duration were included in the analyses and both suggested improvement with effective CPAP therapy [7,8]. Various randomized and nonrandomized studies also have addressed the impact of CPAP 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.009
therapy on endothelial dysfunction, and again there was overwhelming evidence of a positive effect with CPAP therapy [9–13]. Recently Kohler et al. [14] also demonstrated a benefit of CPAP therapy on endothelial function in minimally symptomatic OSA patients. Given this ample evidence of beneficial effects of CPAP therapy on early vascular alterations, how can the lack of benefit of CPAP therapy in the current study [4] be explained? First, the study population used here differs in various aspects from those of previous studies. In contrast to earlier studies, the authors exclusively included subjects without known CVD, hence diminishing the potential adverse effect of confounding variables. However, most importantly is the selection of a cohort with less severe disease, which is in striking contrast to most previous reports. Looking beyond the apnea–hypopnea index as the traditional severity marker, the indices of the nocturnal oximetry of a mean oxygen desaturation index of 9.3 and a minimal saturation of 86% suggest rather mild disease. This finding is of great importance, as IH has been identified to be the main driver of CVD processes in OSA. In mice susceptible to atherosclerosis, IH leads to a significant acceleration of this process associated with systemic and local inflammation [15]. Using a cell culture model, we demonstrated a preferential activation of inflammatory over adaptive pathways by IH [16], and there is growing evidence of systemic inflammation in OSA patients in comparison to matched control subjects [17,18]. Moreover, IH contributes to sympathetic activation and oxidative stress, thus providing a crucial link between the disease and early vascular alterations and subsequent adverse consequences [2]. In long-term outcome studies, OSA in the mild to moderate severity category did not result in increased cardiovascular morbidity and mortality [19], and hence it might be difficult to detect benefits of CPAP therapy on vascular dysfunction in this group. Second, only 40% of included subjects demonstrated adequate CPAP compliance of at least 4 h per night, which was acknowledged as a potential limitation by the authors. Thus the study might be underpowered, particularly given the already mild nature of disease. Third, also adding to the potential problem of power, the study employs measurement of vascular response to inhaled salbutamol by PWA as a technique to assess endothelial function. Although widely used in clinical studies, this technique is known to be less reproducible than flow-mediated dilatation; furthermore, as a consequence, cohorts based on PWA must be larger than those using flow-mediated dilatation to achieve the same power to detect a given effect size [20]. These reservations notwithstanding, the study by Jones et al. [4] adds to the field of impaired vascular function in OSA. For the first time on this research subject the authors explored a crossover
1232
Editorial / Sleep Medicine 14 (2013) 1231–1232
design, thus reducing the potential influence of confounding variables. Comorbidities frequently occur in OSA patients, and adequate matching to control for these confounders often remains unsuccessful. A design like this, preferably with a sufficient washout period, therefore is an attractive approach and should be further explored in future studies. Again, the study raises the question of the minimally necessary treatment duration. The principal factors that will likely influence this point include severity of disease, cardiovascular comorbidities, smoking status, and medication; however, other important factors will include unquantifiable variables, such as duration of OSA prior to diagnosis. Most studies in the field have included small numbers and used different designs and treatment durations. Hence there is a clear need for large, multicenter, randomized, controlled studies evaluating the vascular system with multiple modalities to determine optimal strategies for treatment of early vascular changes and prevention of fatal cardiovascular events in OSA patients. For now, many questions remain unanswered.
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.2013.09.009. References [1] Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013 [Epub ahead of print]. [2] McNicholas WT, Bonsigore MR. Management Committee of EU COST ACTION B26. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29(1):156–78. Epub 2007/01/02. [3] Lévy P, Ryan S, Oldenburg O, Parati G. Sleep apnoea and the heart. Eur Respir Rev 2013;22:333–52. [4] Jones A, Vennelle M, Connell M, McKillop G, Newby D, Douglas N, et al. The effect of continuous positive airway pressure therapy on arterial stiffness and endothelial function in obstructive sleep apnea: a randomized controlled trial in patients without cardiovascular disease. Sleep Med 2013;14:1260–5. [5] Phillips CL, Butlin M, Wong KK, Avolio AP. Is obstructive sleep apnoea causally related to arterial stiffness? a critical review of the experimental evidence. Sleep Med Rev 2013;17:7–18 [published online ahead of print June 1, 2012]. [6] Vlachantoni IT, Dikaiakou E, Antonopoulos CN, Stefanadis C, Daskalopoulou SS, Petridou ET. Effects of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea in arterial stiffness: a meta-analysis. Sleep Med Rev 2013;17:19–28 [published online ahead of print May 9, 2012]. [7] Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:706–12 [published online ahead of print June 7, 2007]. [8] Kohler M, Pepperell JC, Casadei B, Craig S, Crosthwaite N, Stradling JR, et al. CPAP and measures of cardiovascular risk in males with OSAS. Eur Respir J 2008;32:1488–96 [published online ahead of print July 24, 2008].
[9] Bayram NA, Ciftci B, Keles T, Durmaz T, Turhan S, Bozkurt E, et al. Endothelial function in normotensive men with obstructive sleep apnea before and 6 months after CPAP treatment. Sleep 2009;32:1257–63. [10] Cross MD, Mills NL, Al-Abri M, Riha R, Vennelle M, Mackay TW, et al. Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial. Thorax 2008;63:578–83 [published online ahead of print April 4, 2008]. [11] Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348–53 [published online ahead of print October 9, 2003]. [12] Oyama J, Yamamoto H, Maeda T, Ito A, Node K, Makino N. Continuous positive airway pressure therapy improves vascular dysfunction and decreases oxidative stress in patients with the metabolic syndrome and obstructive sleep apnea syndrome. Clin Cardiol 2012;35:231–6 [published online ahead of print January 25, 2012]. [13] Simpson PJ, Hoyos CM, Celermajer D, Liu PY, Ng MK. Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: a randomised sham-controlled study. Int J Cardiol 2013. http://dx.doi.org/10.1016/j.ijcard.2013.01.166 [Epub ahead of print]. [14] Kohler M, Craig S, Pepperell JC, Nicoll D, Bratton DJ, Nunn AJ, et al. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Chest 2013;144:896–902. [15] Arnaud C, Poulain L, Levy P, Dematteis M. Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knockout mice. Atherosclerosis 2011;219:425–31 [published online ahead of print August 31, 2011]. [16] Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7. [17] Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factorkappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–30 [published online ahead of print July 13, 2006]. [18] Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax 2009;64:631–6. [19] 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. [20] Donald AE, Charakida M, Cole TJ, Friberg P, Chowienczyk PJ, Millasseau SC, et al. Non-invasive assessment of endothelial function: which technique. J Am Coll Cardiol 2006;48:1846–50 [published online ahead of print October 17, 2006].
⇑
Silke Ryan Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin, Ireland School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland ⇑ Address: Department of Respiratory Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Tel.: +353 1 277 3702; fax: +353 1 269 7949. E-mail address: [email protected] Available online 12 October 2013
Contents lists available at ScienceDirect
Sleep Medicine journal homepage: www.elsevier.com/locate/sleep
Editorial
The effect of continuous positive airway pressure therapy on vascular function in obstructive sleep apnea: how much is enough? Over the last two decades, obstructive sleep apnea (OSA) has emerged as a considerable public health burden. Due to the ongoing epidemic of obesity, which is strongly linked to OSA, the prevalence of the disease has been steadily rising. According to recent data from the Wisconsin Sleep Cohort, the combination of sleepdisordered breathing as indicated by an apnea–hypopnea index of >5 events per hour and excessive daytime sleepiness occurs in approximately 14% of men and 5% of women between the ages of 30 and 70 years [1]. Cardiovascular diseases (CVDs) represent the principal morbidity and mortality in OSA and large-scale epidemiologic studies have demonstrated an independent relationship between OSA and various cardiac disorders, such as systemic arterial hypertension, ischemic heart disease, heart failure, and stroke [2]. OSA comprises various pathophysiologic triggers for CVD processes including, in particular, intermittent hypoxia (IH) but also sleep fragmentation, intrathoracic pressure swings, and recurrent hypercapnia. These processes in turn have been linked to sympathetic nervous system activity, systemic inflammation, oxidative stress, and possibly metabolic dysfunction as the major pathways in the initiation and progression of CVDs in OSA [3]. Importantly, OSA has been associated with subclinical early alterations in vascular function such as arterial stiffness and endothelial dysfunction. Identification of these early markers of atherosclerosis may be critical, as therapeutic intervention at this stage may prevent the occurrence of major cardiovascular events such as myocardial infarction or stroke. Hence the determination of the efficacy of continuous positive airway pressure (CPAP) therapy in these processes in OSA is of major importance. In this issue of Sleep Medicine, Jones et al. [4] investigate the impact of CPAP therapy on vascular stiffness and endothelial dysfunction in OSA patients without overt CVD using a randomized crossover design. Various evaluation procedures are used in this study, including measurement of augmentation index by pulse wave analysis (PWA) and change with salbutamol or glyceryl trinitrate, pulse wave velocity analysis, and measurement of aortic distensibility by magnetic resonance imaging. The main finding of the study was a trend toward reduced augmentation index with CPAP therapy; however, there was no effect of CPAP therapy on endothelial function, aortic distensibility, and pulse wave velocity. The efficacy of CPAP therapy on arterial stiffness has recently been the subject of two meta-analyses, with both reporting a remarkably concordant improvement with CPAP therapy [5,6]. Two randomized controlled trials of 1 month and 4 months’ duration were included in the analyses and both suggested improvement with effective CPAP therapy [7,8]. Various randomized and nonrandomized studies also have addressed the impact of CPAP 1389-9457/$ - see front matter Ó 2013 Elsevier B.V. All rights reserved. http://dx.doi.org/10.1016/j.sleep.2013.09.009
therapy on endothelial dysfunction, and again there was overwhelming evidence of a positive effect with CPAP therapy [9–13]. Recently Kohler et al. [14] also demonstrated a benefit of CPAP therapy on endothelial function in minimally symptomatic OSA patients. Given this ample evidence of beneficial effects of CPAP therapy on early vascular alterations, how can the lack of benefit of CPAP therapy in the current study [4] be explained? First, the study population used here differs in various aspects from those of previous studies. In contrast to earlier studies, the authors exclusively included subjects without known CVD, hence diminishing the potential adverse effect of confounding variables. However, most importantly is the selection of a cohort with less severe disease, which is in striking contrast to most previous reports. Looking beyond the apnea–hypopnea index as the traditional severity marker, the indices of the nocturnal oximetry of a mean oxygen desaturation index of 9.3 and a minimal saturation of 86% suggest rather mild disease. This finding is of great importance, as IH has been identified to be the main driver of CVD processes in OSA. In mice susceptible to atherosclerosis, IH leads to a significant acceleration of this process associated with systemic and local inflammation [15]. Using a cell culture model, we demonstrated a preferential activation of inflammatory over adaptive pathways by IH [16], and there is growing evidence of systemic inflammation in OSA patients in comparison to matched control subjects [17,18]. Moreover, IH contributes to sympathetic activation and oxidative stress, thus providing a crucial link between the disease and early vascular alterations and subsequent adverse consequences [2]. In long-term outcome studies, OSA in the mild to moderate severity category did not result in increased cardiovascular morbidity and mortality [19], and hence it might be difficult to detect benefits of CPAP therapy on vascular dysfunction in this group. Second, only 40% of included subjects demonstrated adequate CPAP compliance of at least 4 h per night, which was acknowledged as a potential limitation by the authors. Thus the study might be underpowered, particularly given the already mild nature of disease. Third, also adding to the potential problem of power, the study employs measurement of vascular response to inhaled salbutamol by PWA as a technique to assess endothelial function. Although widely used in clinical studies, this technique is known to be less reproducible than flow-mediated dilatation; furthermore, as a consequence, cohorts based on PWA must be larger than those using flow-mediated dilatation to achieve the same power to detect a given effect size [20]. These reservations notwithstanding, the study by Jones et al. [4] adds to the field of impaired vascular function in OSA. For the first time on this research subject the authors explored a crossover
1232
Editorial / Sleep Medicine 14 (2013) 1231–1232
design, thus reducing the potential influence of confounding variables. Comorbidities frequently occur in OSA patients, and adequate matching to control for these confounders often remains unsuccessful. A design like this, preferably with a sufficient washout period, therefore is an attractive approach and should be further explored in future studies. Again, the study raises the question of the minimally necessary treatment duration. The principal factors that will likely influence this point include severity of disease, cardiovascular comorbidities, smoking status, and medication; however, other important factors will include unquantifiable variables, such as duration of OSA prior to diagnosis. Most studies in the field have included small numbers and used different designs and treatment durations. Hence there is a clear need for large, multicenter, randomized, controlled studies evaluating the vascular system with multiple modalities to determine optimal strategies for treatment of early vascular changes and prevention of fatal cardiovascular events in OSA patients. For now, many questions remain unanswered.
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.2013.09.009. References [1] Peppard PE, Young T, Barnet JH, Palta M, Hagen EW, Hla KM. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol 2013 [Epub ahead of print]. [2] McNicholas WT, Bonsigore MR. Management Committee of EU COST ACTION B26. Sleep apnoea as an independent risk factor for cardiovascular disease: current evidence, basic mechanisms and research priorities. Eur Respir J 2007;29(1):156–78. Epub 2007/01/02. [3] Lévy P, Ryan S, Oldenburg O, Parati G. Sleep apnoea and the heart. Eur Respir Rev 2013;22:333–52. [4] Jones A, Vennelle M, Connell M, McKillop G, Newby D, Douglas N, et al. The effect of continuous positive airway pressure therapy on arterial stiffness and endothelial function in obstructive sleep apnea: a randomized controlled trial in patients without cardiovascular disease. Sleep Med 2013;14:1260–5. [5] Phillips CL, Butlin M, Wong KK, Avolio AP. Is obstructive sleep apnoea causally related to arterial stiffness? a critical review of the experimental evidence. Sleep Med Rev 2013;17:7–18 [published online ahead of print June 1, 2012]. [6] Vlachantoni IT, Dikaiakou E, Antonopoulos CN, Stefanadis C, Daskalopoulou SS, Petridou ET. Effects of continuous positive airway pressure (CPAP) treatment for obstructive sleep apnea in arterial stiffness: a meta-analysis. Sleep Med Rev 2013;17:19–28 [published online ahead of print May 9, 2012]. [7] Drager LF, Bortolotto LA, Figueiredo AC, Krieger EM, Lorenzi GF. Effects of continuous positive airway pressure on early signs of atherosclerosis in obstructive sleep apnea. Am J Respir Crit Care Med 2007;176:706–12 [published online ahead of print June 7, 2007]. [8] Kohler M, Pepperell JC, Casadei B, Craig S, Crosthwaite N, Stradling JR, et al. CPAP and measures of cardiovascular risk in males with OSAS. Eur Respir J 2008;32:1488–96 [published online ahead of print July 24, 2008].
[9] Bayram NA, Ciftci B, Keles T, Durmaz T, Turhan S, Bozkurt E, et al. Endothelial function in normotensive men with obstructive sleep apnea before and 6 months after CPAP treatment. Sleep 2009;32:1257–63. [10] Cross MD, Mills NL, Al-Abri M, Riha R, Vennelle M, Mackay TW, et al. Continuous positive airway pressure improves vascular function in obstructive sleep apnoea/hypopnoea syndrome: a randomised controlled trial. Thorax 2008;63:578–83 [published online ahead of print April 4, 2008]. [11] Ip MS, Tse HF, Lam B, Tsang KW, Lam WK. Endothelial function in obstructive sleep apnea and response to treatment. Am J Respir Crit Care Med 2004;169:348–53 [published online ahead of print October 9, 2003]. [12] Oyama J, Yamamoto H, Maeda T, Ito A, Node K, Makino N. Continuous positive airway pressure therapy improves vascular dysfunction and decreases oxidative stress in patients with the metabolic syndrome and obstructive sleep apnea syndrome. Clin Cardiol 2012;35:231–6 [published online ahead of print January 25, 2012]. [13] Simpson PJ, Hoyos CM, Celermajer D, Liu PY, Ng MK. Effects of continuous positive airway pressure on endothelial function and circulating progenitor cells in obstructive sleep apnoea: a randomised sham-controlled study. Int J Cardiol 2013. http://dx.doi.org/10.1016/j.ijcard.2013.01.166 [Epub ahead of print]. [14] Kohler M, Craig S, Pepperell JC, Nicoll D, Bratton DJ, Nunn AJ, et al. CPAP improves endothelial function in patients with minimally symptomatic OSA: results from a subset study of the MOSAIC trial. Chest 2013;144:896–902. [15] Arnaud C, Poulain L, Levy P, Dematteis M. Inflammation contributes to the atherogenic role of intermittent hypoxia in apolipoprotein-E knockout mice. Atherosclerosis 2011;219:425–31 [published online ahead of print August 31, 2011]. [16] Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation 2005;112:2660–7. [17] Ryan S, Taylor CT, McNicholas WT. Predictors of elevated nuclear factorkappaB-dependent genes in obstructive sleep apnea syndrome. Am J Respir Crit Care Med 2006;174:824–30 [published online ahead of print July 13, 2006]. [18] Ryan S, Taylor CT, McNicholas WT. Systemic inflammation: a key factor in the pathogenesis of cardiovascular complications in obstructive sleep apnoea syndrome? Thorax 2009;64:631–6. [19] 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. [20] Donald AE, Charakida M, Cole TJ, Friberg P, Chowienczyk PJ, Millasseau SC, et al. Non-invasive assessment of endothelial function: which technique. J Am Coll Cardiol 2006;48:1846–50 [published online ahead of print October 17, 2006].
⇑
Silke Ryan Pulmonary and Sleep Disorders Unit, St. Vincent’s University Hospital, Dublin, Ireland School of Medicine and Medical Science, The Conway Institute, University College Dublin, Ireland ⇑ Address: Department of Respiratory Medicine, St. Vincent’s University Hospital, Elm Park, Dublin 4, Ireland. Tel.: +353 1 277 3702; fax: +353 1 269 7949. E-mail address: [email protected] Available online 12 October 2013
