EDITORIALS pollution, or do gaseous pollutants such as CO and NO2 play a role? What is the role of ultrafine particles or primary versus secondary particles? Is it true that there remain significant and measurable health effects of air pollution, especially in metropolitan areas with relatively clean air that meets current air quality standards? If so, what can or should we do next? n Author disclosures are available with the text of this article at www.atsjournals.org. C. Arden Pope III, Ph.D. Department of Economics Brigham Young University Provo, Utah
References 1. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;542–549. 2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645–1648. 3. Holland WW, Reid DD. The urban factor in chronic bronchitis. Lancet 1965;1:445–448. 4. Tashkin DP, Detels R, Simmons M, Liu H, Coulson AH, Sayre J, Rokaw S. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am J Respir Crit Care Med 1994;149:1209–1217. 5. Hoek G, Dockery DW, Pope A III, Neas L, Roemer W, Brunekreef B. Association between PM10 and decrements in peak expiratory flow rates in children: reanalysis of data from five panel studies. Eur Respir J 1998;11:1307–1311. 6. Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O’Connor GT, Mittleman MA. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013;188:1351–1357.
7. Lepeule J, Bind MA, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study. Environ Health Perspect 2014;122: 566–572. 8. Urman R, McConnell R, Islam T, Avol EL, Lurmann FW, Vora H, Linn WS, Rappaport EB, Gilliland FD, Gauderman WJ. Associations of children’s lung function with ambient air pollution: joint effects of regional and near-roadway pollutants. Thorax 2014;69:540–547. 9. Gan WQ, FitzGerald JM, Carlsten C, Sadatsafavi M, Brauer M. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013;187:721–727. 10. Pope CA III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109: 71–77. 11. Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, DiezRoux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, et al.; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–2378. 12. Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127:1952–1959. 13. van Eeden SF, Yeung A, Quinlam K, Hogg JC. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:61–67. 14. Lepeule J, Baccarelli A, Motta V, Cantone L, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J, Schwartz J. Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study. Epigenetics 2012;7:261–269.
Copyright © 2014 by the American Thoracic Society
Sleep Apnea, Continuous Positive Airway Pressure, and Renal Health Robust epidemiological evidence links obstructive sleep apnea (OSA) with a number of cardiovascular conditions. Based on population studies, OSA increases the risk of congestive heart failure, hypertension, stroke, and certain arrhythmias and worsens the prognosis of coronary artery disease (1–4). Salutary effects of continuous positive airway pressure (CPAP) therapy on cardiovascular conditions are also well known. Usage of CPAP by patients with OSA leads to a reduction in blood pressure (5), improvement of left ventricular function (6), and reduction of risk of cardiovascular events (3). Less well known is an equally important, bidirectional association between OSA and chronic kidney disease (CKD). While the prevalence of OSA rises as the severity of CKD worsens (to .50% in end-stage renal disease), the rate of glomerular filtration rate decline increases with worsening of nocturnal desaturations typical of sleep apnea (7, 8). Mechanisms of these deleterious effects of nocturnal hypoxemia are believed to involve generation of reactive oxygen species, direct activation of the sympathetic nervous system, and activation of the renin486
angiotensin system (RAS), resulting in an inflammatory response and endothelial cell dysfunction. On a functional level, these processes result in glomerular hyperfiltration, a correlate of proteinuria and glomerular filtration rate (GFR) decrease (9, 10). Usage of CPAP therapy may improve glomerular hyperfiltration (10). In this issue of the Journal, the article by Nicholl and colleagues (pp. 572–580) adds an important piece of information to our understanding of the role of renal RAS in mediating these beneficial changes of CPAP (11). The authors presented a novel observation that a compliant usage of CPAP improved hyperfiltration in a small group of 20 patients with at least moderate OSA and well-controlled hypertension. Compared with pretreatment values, CPAP therapy resulted in a significant decrease of GFR, a borderline increase of renal plasma flow, and, in consequence, a significant, beneficial decrease of the filtration fraction. Two additional positive effects—a significant drop in renal vascular resistance and a decrease in urinary albumin excretion—were also noted. An elevated response to angiotensin II challenge suggested that these positive effects were mediated by
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 5 | September 1 2014
EDITORIALS down-regulation of renal RAS. Although not invalidating the results of the study, a small sample size of just 20 patients was its major limitation. Another striking feature of the research protocol was the way the authors assured CPAP compliance before subjects’ completing the study—the subjects had to fulfill the 4 h/70% of nights criterion, and it took in some cases more than 8 months of CPAP therapy to do so. Although statistically troubling, it made sense on a practical level, as the authors were most concerned about the effects of the sustained and compliant CPAP therapy. Another important finding of the study was the CPAP-induced decrease of serum aldosterone level, an effect that was seen in some (12) but not other prior investigations (13); the lack of uniformity of this prior research was likely due to heterogeneity of patient populations tested and variable degrees of preexisting RAS suppression. An important role in aldosterone blockade for cardiovascular outcomes has been well defined and accepted (14). Although this study extends our knowledge about the pathophysiology of OSA-related renal disease and the beneficial effects of CPAP, it is not clear how applicable these findings are in clinical practice. Nicholl and colleagues performed their study in patients with high normal GFR on high-salt diets who were not taking medication affecting the RAS. The question arises whether similarly positive renoprotective effects of CPAP would be obtained in a more real-life population after dietary sodium restriction, on medications affecting RAS, and with a degree of kidney function impairment. Indeed, data by Kinebuchi and colleagues indicate that patients with adequate blockade of the RAS system may not experience similar beneficial effects of CPAP on hyperfiltration as those without the blockade (10). In spite of questions about clinical applicability of the data of Nicholl and colleagues, we are glad to see the publication of this study, as it attempts to fill in the scientific gap and explore an association of OSA and kidney disease. Based on the population studies, much is known about relationships between OSA and other components of the metabolic syndrome. However, a multitude of intermediary, mutually interconnected mechanisms through which OSA affects health make exploration of these associations difficult, both on a population level and on a molecular one (15). Defining these processes has been especially difficult in the area of renal vascular bed injury, due to the lack of easily measurable outcomes that might precisely reflect an acute effect of local RAS activation, vascular oxidative stress, endothelial dysfunction, and other intermediary mechanisms. Because it is plausible that apnea-induced intermittent episodes of nocturnal hypoxemia add acute kidney injury events to the CKD process, an investigation of possible effects of CPAP on acute kidney injury biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), or liver-type fatty acid–binding protein (L-FABP), seems to be a valuable object of further research (16). It could bring new evidence on a potential positive impact of CPAP treatment on the renal tubule structure, extending the observations of Nicholl and colleagues of its functional influence on the RAS. n Author disclosures are available with the text of this article at www.atsjournals.org. Tomasz J. Kuźniar, M.D., Ph.D. Division of Pulmonary and Critical Care Medicine NorthShore University HealthSystem Evanston, Illinois
Editorials
Marian Klinger, M.D., Ph.D. Department of Nephrology and Transplantation Medicine Wrocław Medical University Wrocław, Poland
References 1. Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, Redline S, Resnick HE, Tong EK, Diener-West M, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352–360. 2. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. 3. 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;365:1046–1053. 4. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. 5. Gottlieb DJ, Punjabi NM, Mehra R, Patel SR, Quan SF, Babineau DC, Tracy RP, Rueschman M, Blumenthal RS, Lewis EF, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276–2285. 6. Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361–366. 7. Sakaguchi Y, Hatta T, Hayashi T, Shoji T, Suzuki A, Tomida K, Okada N, Rakugi H, Isaka Y, Tsubakihara Y. Association of nocturnal hypoxemia with progression of CKD. Clin J Am Soc Nephrol 2013;8:1502–1507. 8. Nicholl DD, Ahmed SB, Loewen AH, Hemmelgarn BR, Sola DY, Beecroft JM, Turin TC, Hanly PJ. Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. Chest 2012;141:1422–1430. 9. Faulx MD, Storfer-Isser A, Kirchner HL, Jenny NS, Tracy RP, Redline S. Obstructive sleep apnea is associated with increased urinary albumin excretion. Sleep 2007;30:923–929. 10. Kinebuchi S, Kazama JJ, Satoh M, Sakai K, Nakayama H, Yoshizawa H, Narita I, Suzuki E, Gejyo F. Short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apnoea syndrome. Clin Sci (Lond) 2004;107:317–322. 11. Nicholl DDM, Hanly PJ, Poulin MJ, Handley GB, Hemmelgarn BR, Sola DY, Ahmed SB. Evaluation of continuous positive airway pressure therapy on renin–angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med 2014;190:572–580. 12. Saarelainen S, Hasan J, Siitonen S, Seppal ¨ a¨ E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 1996;5:181–185. 13. Meston N, Davies RJ, Mullins R, Jenkinson C, Wass JA, Stradling JR. Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med 2003;254:447–454. 14. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 15. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290: 1906–1914. 16. Murase K, Mori K, Yoshimura C, Aihara K, Chihara Y, Azuma M, Harada Y, Toyama Y, Tanizawa K, Handa T, et al. Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia. PLoS ONE 2013;8:e54184.
Copyright © 2014 by the American Thoracic Society
487
References 1. Lepeule J, Litonjua AA, Coull B, Koutrakis P, Sparrow D, Vokonas PS, Schwartz J. Long-term effects of traffic particles on lung function decline in the elderly. Am J Respir Crit Care Med 2014;542–549. 2. Fletcher C, Peto R. The natural history of chronic airflow obstruction. BMJ 1977;1:1645–1648. 3. Holland WW, Reid DD. The urban factor in chronic bronchitis. Lancet 1965;1:445–448. 4. Tashkin DP, Detels R, Simmons M, Liu H, Coulson AH, Sayre J, Rokaw S. The UCLA population studies of chronic obstructive respiratory disease: XI. Impact of air pollution and smoking on annual change in forced expiratory volume in one second. Am J Respir Crit Care Med 1994;149:1209–1217. 5. Hoek G, Dockery DW, Pope A III, Neas L, Roemer W, Brunekreef B. Association between PM10 and decrements in peak expiratory flow rates in children: reanalysis of data from five panel studies. Eur Respir J 1998;11:1307–1311. 6. Rice MB, Ljungman PL, Wilker EH, Gold DR, Schwartz JD, Koutrakis P, Washko GR, O’Connor GT, Mittleman MA. Short-term exposure to air pollution and lung function in the Framingham Heart Study. Am J Respir Crit Care Med 2013;188:1351–1357.
7. Lepeule J, Bind MA, Baccarelli AA, Koutrakis P, Tarantini L, Litonjua A, Sparrow D, Vokonas P, Schwartz JD. Epigenetic influences on associations between air pollutants and lung function in elderly men: the normative aging study. Environ Health Perspect 2014;122: 566–572. 8. Urman R, McConnell R, Islam T, Avol EL, Lurmann FW, Vora H, Linn WS, Rappaport EB, Gilliland FD, Gauderman WJ. Associations of children’s lung function with ambient air pollution: joint effects of regional and near-roadway pollutants. Thorax 2014;69:540–547. 9. Gan WQ, FitzGerald JM, Carlsten C, Sadatsafavi M, Brauer M. Associations of ambient air pollution with chronic obstructive pulmonary disease hospitalization and mortality. Am J Respir Crit Care Med 2013;187:721–727. 10. Pope CA III, Burnett RT, Thurston GD, Thun MJ, Calle EE, Krewski D, Godleski JJ. Cardiovascular mortality and long-term exposure to particulate air pollution: epidemiological evidence of general pathophysiological pathways of disease. Circulation 2004;109: 71–77. 11. Brook RD, Rajagopalan S, Pope CA III, Brook JR, Bhatnagar A, DiezRoux AV, Holguin F, Hong Y, Luepker RV, Mittleman MA, et al.; American Heart Association Council on Epidemiology and Prevention, Council on the Kidney in Cardiovascular Disease, and Council on Nutrition, Physical Activity and Metabolism. Particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the American Heart Association. Circulation 2010;121:2331–2378. 12. Sin DD, Wu L, Man SFP. The relationship between reduced lung function and cardiovascular mortality: a population-based study and a systematic review of the literature. Chest 2005;127:1952–1959. 13. van Eeden SF, Yeung A, Quinlam K, Hogg JC. Systemic response to ambient particulate matter: relevance to chronic obstructive pulmonary disease. Proc Am Thorac Soc 2005;2:61–67. 14. Lepeule J, Baccarelli A, Motta V, Cantone L, Litonjua AA, Sparrow D, Vokonas PS, Schwartz J, Schwartz J. Gene promoter methylation is associated with lung function in the elderly: the Normative Aging Study. Epigenetics 2012;7:261–269.
Copyright © 2014 by the American Thoracic Society
Sleep Apnea, Continuous Positive Airway Pressure, and Renal Health Robust epidemiological evidence links obstructive sleep apnea (OSA) with a number of cardiovascular conditions. Based on population studies, OSA increases the risk of congestive heart failure, hypertension, stroke, and certain arrhythmias and worsens the prognosis of coronary artery disease (1–4). Salutary effects of continuous positive airway pressure (CPAP) therapy on cardiovascular conditions are also well known. Usage of CPAP by patients with OSA leads to a reduction in blood pressure (5), improvement of left ventricular function (6), and reduction of risk of cardiovascular events (3). Less well known is an equally important, bidirectional association between OSA and chronic kidney disease (CKD). While the prevalence of OSA rises as the severity of CKD worsens (to .50% in end-stage renal disease), the rate of glomerular filtration rate decline increases with worsening of nocturnal desaturations typical of sleep apnea (7, 8). Mechanisms of these deleterious effects of nocturnal hypoxemia are believed to involve generation of reactive oxygen species, direct activation of the sympathetic nervous system, and activation of the renin486
angiotensin system (RAS), resulting in an inflammatory response and endothelial cell dysfunction. On a functional level, these processes result in glomerular hyperfiltration, a correlate of proteinuria and glomerular filtration rate (GFR) decrease (9, 10). Usage of CPAP therapy may improve glomerular hyperfiltration (10). In this issue of the Journal, the article by Nicholl and colleagues (pp. 572–580) adds an important piece of information to our understanding of the role of renal RAS in mediating these beneficial changes of CPAP (11). The authors presented a novel observation that a compliant usage of CPAP improved hyperfiltration in a small group of 20 patients with at least moderate OSA and well-controlled hypertension. Compared with pretreatment values, CPAP therapy resulted in a significant decrease of GFR, a borderline increase of renal plasma flow, and, in consequence, a significant, beneficial decrease of the filtration fraction. Two additional positive effects—a significant drop in renal vascular resistance and a decrease in urinary albumin excretion—were also noted. An elevated response to angiotensin II challenge suggested that these positive effects were mediated by
American Journal of Respiratory and Critical Care Medicine Volume 190 Number 5 | September 1 2014
EDITORIALS down-regulation of renal RAS. Although not invalidating the results of the study, a small sample size of just 20 patients was its major limitation. Another striking feature of the research protocol was the way the authors assured CPAP compliance before subjects’ completing the study—the subjects had to fulfill the 4 h/70% of nights criterion, and it took in some cases more than 8 months of CPAP therapy to do so. Although statistically troubling, it made sense on a practical level, as the authors were most concerned about the effects of the sustained and compliant CPAP therapy. Another important finding of the study was the CPAP-induced decrease of serum aldosterone level, an effect that was seen in some (12) but not other prior investigations (13); the lack of uniformity of this prior research was likely due to heterogeneity of patient populations tested and variable degrees of preexisting RAS suppression. An important role in aldosterone blockade for cardiovascular outcomes has been well defined and accepted (14). Although this study extends our knowledge about the pathophysiology of OSA-related renal disease and the beneficial effects of CPAP, it is not clear how applicable these findings are in clinical practice. Nicholl and colleagues performed their study in patients with high normal GFR on high-salt diets who were not taking medication affecting the RAS. The question arises whether similarly positive renoprotective effects of CPAP would be obtained in a more real-life population after dietary sodium restriction, on medications affecting RAS, and with a degree of kidney function impairment. Indeed, data by Kinebuchi and colleagues indicate that patients with adequate blockade of the RAS system may not experience similar beneficial effects of CPAP on hyperfiltration as those without the blockade (10). In spite of questions about clinical applicability of the data of Nicholl and colleagues, we are glad to see the publication of this study, as it attempts to fill in the scientific gap and explore an association of OSA and kidney disease. Based on the population studies, much is known about relationships between OSA and other components of the metabolic syndrome. However, a multitude of intermediary, mutually interconnected mechanisms through which OSA affects health make exploration of these associations difficult, both on a population level and on a molecular one (15). Defining these processes has been especially difficult in the area of renal vascular bed injury, due to the lack of easily measurable outcomes that might precisely reflect an acute effect of local RAS activation, vascular oxidative stress, endothelial dysfunction, and other intermediary mechanisms. Because it is plausible that apnea-induced intermittent episodes of nocturnal hypoxemia add acute kidney injury events to the CKD process, an investigation of possible effects of CPAP on acute kidney injury biomarkers, such as neutrophil gelatinase-associated lipocalin (NGAL), kidney injury molecule-1 (KIM-1), or liver-type fatty acid–binding protein (L-FABP), seems to be a valuable object of further research (16). It could bring new evidence on a potential positive impact of CPAP treatment on the renal tubule structure, extending the observations of Nicholl and colleagues of its functional influence on the RAS. n Author disclosures are available with the text of this article at www.atsjournals.org. Tomasz J. Kuźniar, M.D., Ph.D. Division of Pulmonary and Critical Care Medicine NorthShore University HealthSystem Evanston, Illinois
Editorials
Marian Klinger, M.D., Ph.D. Department of Nephrology and Transplantation Medicine Wrocław Medical University Wrocław, Poland
References 1. Gottlieb DJ, Yenokyan G, Newman AB, O’Connor GT, Punjabi NM, Quan SF, Redline S, Resnick HE, Tong EK, Diener-West M, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation 2010;122:352–360. 2. Peppard PE, Young T, Palta M, Skatrud J. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med 2000;342:1378–1384. 3. 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;365:1046–1053. 4. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, O’Connor GT, Boland LL, Schwartz JE, Samet JM. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med 2001;163:19–25. 5. Gottlieb DJ, Punjabi NM, Mehra R, Patel SR, Quan SF, Babineau DC, Tracy RP, Rueschman M, Blumenthal RS, Lewis EF, et al. CPAP versus oxygen in obstructive sleep apnea. N Engl J Med 2014;370:2276–2285. 6. Mansfield DR, Gollogly NC, Kaye DM, Richardson M, Bergin P, Naughton MT. Controlled trial of continuous positive airway pressure in obstructive sleep apnea and heart failure. Am J Respir Crit Care Med 2004;169:361–366. 7. Sakaguchi Y, Hatta T, Hayashi T, Shoji T, Suzuki A, Tomida K, Okada N, Rakugi H, Isaka Y, Tsubakihara Y. Association of nocturnal hypoxemia with progression of CKD. Clin J Am Soc Nephrol 2013;8:1502–1507. 8. Nicholl DD, Ahmed SB, Loewen AH, Hemmelgarn BR, Sola DY, Beecroft JM, Turin TC, Hanly PJ. Declining kidney function increases the prevalence of sleep apnea and nocturnal hypoxia. Chest 2012;141:1422–1430. 9. Faulx MD, Storfer-Isser A, Kirchner HL, Jenny NS, Tracy RP, Redline S. Obstructive sleep apnea is associated with increased urinary albumin excretion. Sleep 2007;30:923–929. 10. Kinebuchi S, Kazama JJ, Satoh M, Sakai K, Nakayama H, Yoshizawa H, Narita I, Suzuki E, Gejyo F. Short-term use of continuous positive airway pressure ameliorates glomerular hyperfiltration in patients with obstructive sleep apnoea syndrome. Clin Sci (Lond) 2004;107:317–322. 11. Nicholl DDM, Hanly PJ, Poulin MJ, Handley GB, Hemmelgarn BR, Sola DY, Ahmed SB. Evaluation of continuous positive airway pressure therapy on renin–angiotensin system activity in obstructive sleep apnea. Am J Respir Crit Care Med 2014;190:572–580. 12. Saarelainen S, Hasan J, Siitonen S, Seppal ¨ a¨ E. Effect of nasal CPAP treatment on plasma volume, aldosterone and 24-h blood pressure in obstructive sleep apnoea. J Sleep Res 1996;5:181–185. 13. Meston N, Davies RJ, Mullins R, Jenkinson C, Wass JA, Stradling JR. Endocrine effects of nasal continuous positive airway pressure in male patients with obstructive sleep apnoea. J Intern Med 2003;254:447–454. 14. Zannad F, McMurray JJ, Krum H, van Veldhuisen DJ, Swedberg K, Shi H, Vincent J, Pocock SJ, Pitt B; EMPHASIS-HF Study Group. Eplerenone in patients with systolic heart failure and mild symptoms. N Engl J Med 2011;364:11–21. 15. Shamsuzzaman AS, Gersh BJ, Somers VK. Obstructive sleep apnea: implications for cardiac and vascular disease. JAMA 2003;290: 1906–1914. 16. Murase K, Mori K, Yoshimura C, Aihara K, Chihara Y, Azuma M, Harada Y, Toyama Y, Tanizawa K, Handa T, et al. Association between plasma neutrophil gelatinase associated lipocalin level and obstructive sleep apnea or nocturnal intermittent hypoxia. PLoS ONE 2013;8:e54184.
Copyright © 2014 by the American Thoracic Society
487
