- Email: [email protected]
Through the ophthalmoscope: New insight into the risk of cardiovascular disease in sleep disordered breathing?
Atherosclerosis 226 (2013) 40e42
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Through the ophthalmoscope: New insight into the risk of cardiovascular disease in sleep disordered breathing? Y. Moodley*, G.F. Watts School of Medicine and Pharmacology, University of Western Australia, 4th floor, MRF Building, 50 Murray Street, Perth 6000, Australia
a r t i c l e i n f o Article history: Received 7 June 2012 Available online 4 July 2012 Keywords: Sleep disordered breathing Retina Retinal changes
Sleep disordered breathing (SDB) is associated with several clinically important cardiometabolic abnormalities. The prevalence of CHD in subjects with SDB is 30e60% [1], risk being highest in those with severe SDB [2]. Severe SDB is also associated with a 3fold increased risk of stroke, particularly in men [3]. Hypertension, dyslipideamia, hyperglycaemia, insulin resistance, diabetes and hyperadrenergic activity are all increased in SDB and may collectively explain the associated high risk of cardiovascular disease [4,5]. The cardiovascular complications of SDB may involve both medium and larger arteries. Little is known about the mechanism by which SDB influences the microvasculature. Computer-assisted imaging of the retinal microcirculation has provided a rich opportunity for investigating the retinal microcirculation and by extension the circulation in other arterial beds [6]. The composite evidence, with some qualifications related to gender and age group, suggests that changes in the caliber of both retinal arteries and veins are significantly and independently predictive of cardiovascular events [7,8]. In this issue of the journal, Shankar et al. [9] report on an investigation of the retinal vessels of subjects with SDB. The authors proposed that microvascular disease is a potential mechanism underlying cardiovascular complications in SDB, and that this can be examined non-invasively, since the retinal microvasculature is structurally and functionally similar to the
DOI of original article: http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.046. * Corresponding author. Tel.: þ61 92240232; fax: þ61 (0)892240345. E-mail addresses: [email protected] (Y. Moodley), gerald.watts@ uwa.edu.au (G.F. Watts). 0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.06.018
microvasculature of other organs. They examined 491 participants from the Wisconsin Sleep Cohort Study. The severity of SDB was characterized by an apnea-hypopnea index (AHI) of <5 events/h, 5e14.9 events/h, or 15 events/h. They investigated the presence of retinal arteriolar narrowing (mean retinal arteriolar diameter < 141.0 mm) and retinal venular widening (mean venular diameter > 223.0 mm) using a standardized computerized method to assess vessel diameter. A higher AHI was found to be positively associated with retinal venular dilatation (RVD), independent of body mass index, hypertension, diabetes, and lipid levels. Compared with an AHI of <5 events/h, the multivariate-adjusted odds ratio for retinal venular widening was 1.31 (0.75e2.28) for an AHI of 5e14.9 events/h, and 2.08 (1.03e2.16) for an AHI of >15 events/h (p-trend ¼ 0.045). In contrast, there was no association between AHI and retinal arteriolar narrowing (p-trend ¼ 0.72). The authors concluded that a higher AHI, a marker of SDB, was positively associated with widening of the retinal venules, independent of conventional cardiovascular risk factors. The authors suggest that cardiovascular disease associated with SDB may be mediated, in part, by microvasculopathy, as reflected by RVD, and this may relate to endothelial dysfunction. This findings need to be contrasted with the earlier report of Boland et al. [10] who in a study of larger sample failed to demonstrate retinal vessel abnormalities in subjects with SDB. However, they employed the arteriolar-to-venule ratio as their endpoint. This summary statistic overlooks that arteriolar narrowing and retinal venous dilation (RVD) are separate phenomena that reflect different pathophysiological processes and need to be quantitated separately [11]. The dose-response relationship between SDB and RVD noted by Shankar et al. is persuasive but
Y. Moodley, G.F. Watts / Atherosclerosis 226 (2013) 40e42
incomplete evidence for a causal association. Differences between the studies may also relate to variation in the approaches for defining SDB, there being at present no standard method for quantifying the severity of sleep apnea. Also, can endothelial dysfunction be a direct and central cause for RVD in SDB? Chronic hypoxia in SDB may result in increase hematocrit, increase blood viscosity and venous dilatation. Local autoregulation to hypoxia to maintain retinal tissue oxygenation may underlying the main finding of the study with RVD being an adaptive rather than a pathological response to the effect of SDB on the retinal microcirculation [12]. The submission of data on hyperviscosity in relation to SDB in the present study might have proved informative. In a wider context, there are several multisystemic causes of RVD and this may relate to both chronic hypoxia and venous obstruction. On the other hand, there is strong evidence for endothelial dysfunction in SDB. Endothelium-dependent vasodilation, as measured by forearm blood flow following intra-arterial infusion of acetylcholine, is reduced in subjects with SDB [8]. In addition, nitric oxide levels and endothelial progenitor cell (EPC) numbers are decreased, and these are both central to endothelial repair. Persons with retinal venular dilatation have reduced flow mediated dilatation of the brachial artery (a conduit artery) that is not explicable by traditional vascular risk, implying another common link with SDB [7]. Whether similar findings extend to the coronary circulation remains to be demonstrated, for in here the link is strongest with retinal arterial narrowing [8]. Arteriolar as opposed to venular narrowing is also more closely associated with hypertension, consistent with the finding of the present study, although blood pressure was not entered into regression analyses as a continuous variable. Randomized studies have demonstrated improvement in endothelial function following continuous positive airway pressure (CPAP) treatment in people with SDB, but whether this is paralleled by reduction in dilated retinal venular diameter has not been reported. While the findings of Shankar et al. [9] are new and plausible, they do not offer convincing mechanistic insights into the pathogenesis of cardiovascular disease in SDB. At a cellular level, the intermittent repetitive hypoxia and re-oxygenation associated with SDB may lead to direct endothelial dysfunction due to reduced eNOS levels and increased production of reactive oxygen species [13]. The increased oxidative stress caused by chronic hypoxia further reduces NO production by decreasing the availability of cofactors for NO synthesis [14]. Oxidant stress, a major source of endothelial injury in SDB, is caused by increases in NADPH and xanthine oxidase activity, and reduced levels of antioxidants and mitochondrial complex-1 [15]. Furthermore, vasoactive factors such as angiotensin II and endothelin-1 cause vasoconstriction, while heightened sympathetic activity results in endothelial injury due to elevation of blood pressure [16]. Furthermore, increased inflammation associated with SDB injures the endothelium. As a consequence of the up-regulation of NF-kB and hypoxia inducible factor, C-reactive protein, interleukin-6 (IL-6), TNF and plasminogen activator inhibitor-1 (PAI-1) levels are increased [5]. Mechanical complications of SDB also cause vascular injury. Intra-thoracic pressure swings due to forced breathing against an obstructed upper airway cause negative intra-thoracic changes of 60 to 80 mmHg, thus inducing shear stress on blood vessels and injuring the endothelium [17]. Dyslipidemia is also associated with SDB, since intermittent hypoxia alters hepatic enzymes, including sterol regulatory element-binding protein-1 (SREBP-1) and phospholipid biosynthesis (stearoyl-CoA desaturase-1) [18]. Is RVD localized to the retina or indicative of more diffuse microvasculopathy? The authors excluded cardiovascular and metabolic causes of RVD in subjects with SDB, but did not explore
41
the role of hyperviscosity nor the full range of atherothrombotic risk factors, including triglyceride-rich lipoproteins, plasminogen activator inhibitor-1 and platelet aggregation. RVD in SDB is probably a direct result of intermittent repetitive hypoxia and reoxygenation, resulting in endothelial damage. The factors mediating endothelial damage in SDB include inflammation, oxidantmediated damage, retinal hypoxia, shear stress and dyslipidaemia. Rheumatoid arthritis is an independent risk factor for CHD mediated by diffuse vascular inflammation, and would be an interesting control disease in future studies of RVD in subjects with SBD. Prospective studies on the relationship between RVD and progression or cardiovascular complications in SDB are highly pertinent to test the hypothesis generating aspects of the study by Shankar et al. Such studies should also explore whether RVD in subjects with SDB is limited to the retina or reflects a more diffuse microvasculopathy. It remains to be demonstrated in larger cohorts whether cardiovascular risk associated with RVD in SDB is dependent of gender, age, ethnicity and genetic factors [6,19]. In diabetics RVD is also likely to be an early marker of retinopathy [7]. RVD may be a marker for complications of respiratory conditions beyond SDB. Chronic obstructive pulmonary disease (COPD) is amongst the top five global causes of morbidity and mortality. It is now increasingly recognized that cardiovascular complications, and not necessarily end-stage respiratory failure, are a major cause of morbidity and mortality in COPD patients. Further studies are needed to investigate whether RVD is an early indicator of cardiovascular risk in COPD and related pulmonary conditions. Finally, despite the interest that the study by Shankar et al. [9], may generate further work is required to explore the mechanisms and role of specific treatments in preventing and reversing the risk of cardiovascular disease in people with SDB [20]. A central question is whether treating sleep apnea decreases cardiovascular events in people with SDB. References [1] Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82e93. [2] Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation; 122: 352e60. [3] 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; 182: 269e77. [4] Di Murro A, Petramala L, Cotesta D, et al. Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism. J Renin Angiotensin Aldosterone Syst; 11: 165e72. [5] Monahan K, Redline S. Role of obstructive sleep apnea in cardiovascular disease. Curr Opin Cardiol; 26: 541e7. [6] Sun C, Wang JJ, Mackey DA, Wong TY. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol 2009;54: 74e95. [7] Nguyen TT, Wang JJ, Islam FM, et al. Retinal arteriolar narrowing predicts incidence of diabetes: the Australian diabetes, obesity and lifestyle (AusDiab) study. Diabetes 2008;57:536e9. [8] Wang JJ, Liew G, Klein R, et al. Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. Eur Heart J 2007; 28:1984e92. [9] Shankar A, Peppard PE, Young T, et al. Sleep-disordered breathing and retinal microvascular diameter. Atherosclerosis 2013;226(1):122e6. [10] Boland LL, Shahar E, Wong TY, et al. Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the sleep heart health study. Sleep 2004;27:467e73. [11] Liew G, Sharrett AR, Kronmal R, et al. Measurement of retinal vascular caliber: issues and alternatives to using the arteriole to venule ratio. Invest Ophthalmol Vis Sci 2007;48:52e7. [12] Brinchmann-Hansen O, Myhre K, Sandvik L. Retinal vessel responses to exercise and hypoxia before and after high altitude acclimatisation. Eye (Lond) 1989;3(Pt 6):768e76. [13] McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 1994;267:H1921e7.
42
Y. Moodley, G.F. Watts / Atherosclerosis 226 (2013) 40e42
[14] Wang P, Zweier JL. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J Biol Chem 1996;271:29223e30. [15] Peng Y, Yuan G, Overholt JL, Kumar GK, Prabhakar NR. Systemic and cellular responses to intermittent hypoxia: evidence for oxidative stress and mitochondrial dysfunction. Adv Exp Med Biol 2003;536:559e64. [16] Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G, Andreas S. Endothelin1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J 2000;15:320e5. [17] Issa FG, Porostocky S, Feroah T. Effect of sleep and sighing on upper airway resistance in mongrel dogs. J Appl Physiol 1994;77:856e61.
[18] Drager LF, Jun J, Polotsky VY. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes; 17: 161e5. [19] McGeechan K, Liew G, Macaskill P, et al. Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med 2009;151:404e13. [20] Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American heart association/American college of cardiology foundation scientific statement from the American heart association council for high blood pressure research professional education committee, council on clinical cardiology, stroke council, and council on cardiovascular nursing. In collaboration with the national heart, lung, and blood institute national center on sleep disorders research (national institutes of health). Circulation 2008;118:1080e111.
Contents lists available at SciVerse ScienceDirect
Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis
Invited commentary
Through the ophthalmoscope: New insight into the risk of cardiovascular disease in sleep disordered breathing? Y. Moodley*, G.F. Watts School of Medicine and Pharmacology, University of Western Australia, 4th floor, MRF Building, 50 Murray Street, Perth 6000, Australia
a r t i c l e i n f o Article history: Received 7 June 2012 Available online 4 July 2012 Keywords: Sleep disordered breathing Retina Retinal changes
Sleep disordered breathing (SDB) is associated with several clinically important cardiometabolic abnormalities. The prevalence of CHD in subjects with SDB is 30e60% [1], risk being highest in those with severe SDB [2]. Severe SDB is also associated with a 3fold increased risk of stroke, particularly in men [3]. Hypertension, dyslipideamia, hyperglycaemia, insulin resistance, diabetes and hyperadrenergic activity are all increased in SDB and may collectively explain the associated high risk of cardiovascular disease [4,5]. The cardiovascular complications of SDB may involve both medium and larger arteries. Little is known about the mechanism by which SDB influences the microvasculature. Computer-assisted imaging of the retinal microcirculation has provided a rich opportunity for investigating the retinal microcirculation and by extension the circulation in other arterial beds [6]. The composite evidence, with some qualifications related to gender and age group, suggests that changes in the caliber of both retinal arteries and veins are significantly and independently predictive of cardiovascular events [7,8]. In this issue of the journal, Shankar et al. [9] report on an investigation of the retinal vessels of subjects with SDB. The authors proposed that microvascular disease is a potential mechanism underlying cardiovascular complications in SDB, and that this can be examined non-invasively, since the retinal microvasculature is structurally and functionally similar to the
DOI of original article: http://dx.doi.org/10.1016/j.atherosclerosis.2012.10.046. * Corresponding author. Tel.: þ61 92240232; fax: þ61 (0)892240345. E-mail addresses: [email protected] (Y. Moodley), gerald.watts@ uwa.edu.au (G.F. Watts). 0021-9150/$ e see front matter Ó 2012 Published by Elsevier Ireland Ltd. http://dx.doi.org/10.1016/j.atherosclerosis.2012.06.018
microvasculature of other organs. They examined 491 participants from the Wisconsin Sleep Cohort Study. The severity of SDB was characterized by an apnea-hypopnea index (AHI) of <5 events/h, 5e14.9 events/h, or 15 events/h. They investigated the presence of retinal arteriolar narrowing (mean retinal arteriolar diameter < 141.0 mm) and retinal venular widening (mean venular diameter > 223.0 mm) using a standardized computerized method to assess vessel diameter. A higher AHI was found to be positively associated with retinal venular dilatation (RVD), independent of body mass index, hypertension, diabetes, and lipid levels. Compared with an AHI of <5 events/h, the multivariate-adjusted odds ratio for retinal venular widening was 1.31 (0.75e2.28) for an AHI of 5e14.9 events/h, and 2.08 (1.03e2.16) for an AHI of >15 events/h (p-trend ¼ 0.045). In contrast, there was no association between AHI and retinal arteriolar narrowing (p-trend ¼ 0.72). The authors concluded that a higher AHI, a marker of SDB, was positively associated with widening of the retinal venules, independent of conventional cardiovascular risk factors. The authors suggest that cardiovascular disease associated with SDB may be mediated, in part, by microvasculopathy, as reflected by RVD, and this may relate to endothelial dysfunction. This findings need to be contrasted with the earlier report of Boland et al. [10] who in a study of larger sample failed to demonstrate retinal vessel abnormalities in subjects with SDB. However, they employed the arteriolar-to-venule ratio as their endpoint. This summary statistic overlooks that arteriolar narrowing and retinal venous dilation (RVD) are separate phenomena that reflect different pathophysiological processes and need to be quantitated separately [11]. The dose-response relationship between SDB and RVD noted by Shankar et al. is persuasive but
Y. Moodley, G.F. Watts / Atherosclerosis 226 (2013) 40e42
incomplete evidence for a causal association. Differences between the studies may also relate to variation in the approaches for defining SDB, there being at present no standard method for quantifying the severity of sleep apnea. Also, can endothelial dysfunction be a direct and central cause for RVD in SDB? Chronic hypoxia in SDB may result in increase hematocrit, increase blood viscosity and venous dilatation. Local autoregulation to hypoxia to maintain retinal tissue oxygenation may underlying the main finding of the study with RVD being an adaptive rather than a pathological response to the effect of SDB on the retinal microcirculation [12]. The submission of data on hyperviscosity in relation to SDB in the present study might have proved informative. In a wider context, there are several multisystemic causes of RVD and this may relate to both chronic hypoxia and venous obstruction. On the other hand, there is strong evidence for endothelial dysfunction in SDB. Endothelium-dependent vasodilation, as measured by forearm blood flow following intra-arterial infusion of acetylcholine, is reduced in subjects with SDB [8]. In addition, nitric oxide levels and endothelial progenitor cell (EPC) numbers are decreased, and these are both central to endothelial repair. Persons with retinal venular dilatation have reduced flow mediated dilatation of the brachial artery (a conduit artery) that is not explicable by traditional vascular risk, implying another common link with SDB [7]. Whether similar findings extend to the coronary circulation remains to be demonstrated, for in here the link is strongest with retinal arterial narrowing [8]. Arteriolar as opposed to venular narrowing is also more closely associated with hypertension, consistent with the finding of the present study, although blood pressure was not entered into regression analyses as a continuous variable. Randomized studies have demonstrated improvement in endothelial function following continuous positive airway pressure (CPAP) treatment in people with SDB, but whether this is paralleled by reduction in dilated retinal venular diameter has not been reported. While the findings of Shankar et al. [9] are new and plausible, they do not offer convincing mechanistic insights into the pathogenesis of cardiovascular disease in SDB. At a cellular level, the intermittent repetitive hypoxia and re-oxygenation associated with SDB may lead to direct endothelial dysfunction due to reduced eNOS levels and increased production of reactive oxygen species [13]. The increased oxidative stress caused by chronic hypoxia further reduces NO production by decreasing the availability of cofactors for NO synthesis [14]. Oxidant stress, a major source of endothelial injury in SDB, is caused by increases in NADPH and xanthine oxidase activity, and reduced levels of antioxidants and mitochondrial complex-1 [15]. Furthermore, vasoactive factors such as angiotensin II and endothelin-1 cause vasoconstriction, while heightened sympathetic activity results in endothelial injury due to elevation of blood pressure [16]. Furthermore, increased inflammation associated with SDB injures the endothelium. As a consequence of the up-regulation of NF-kB and hypoxia inducible factor, C-reactive protein, interleukin-6 (IL-6), TNF and plasminogen activator inhibitor-1 (PAI-1) levels are increased [5]. Mechanical complications of SDB also cause vascular injury. Intra-thoracic pressure swings due to forced breathing against an obstructed upper airway cause negative intra-thoracic changes of 60 to 80 mmHg, thus inducing shear stress on blood vessels and injuring the endothelium [17]. Dyslipidemia is also associated with SDB, since intermittent hypoxia alters hepatic enzymes, including sterol regulatory element-binding protein-1 (SREBP-1) and phospholipid biosynthesis (stearoyl-CoA desaturase-1) [18]. Is RVD localized to the retina or indicative of more diffuse microvasculopathy? The authors excluded cardiovascular and metabolic causes of RVD in subjects with SDB, but did not explore
41
the role of hyperviscosity nor the full range of atherothrombotic risk factors, including triglyceride-rich lipoproteins, plasminogen activator inhibitor-1 and platelet aggregation. RVD in SDB is probably a direct result of intermittent repetitive hypoxia and reoxygenation, resulting in endothelial damage. The factors mediating endothelial damage in SDB include inflammation, oxidantmediated damage, retinal hypoxia, shear stress and dyslipidaemia. Rheumatoid arthritis is an independent risk factor for CHD mediated by diffuse vascular inflammation, and would be an interesting control disease in future studies of RVD in subjects with SBD. Prospective studies on the relationship between RVD and progression or cardiovascular complications in SDB are highly pertinent to test the hypothesis generating aspects of the study by Shankar et al. Such studies should also explore whether RVD in subjects with SDB is limited to the retina or reflects a more diffuse microvasculopathy. It remains to be demonstrated in larger cohorts whether cardiovascular risk associated with RVD in SDB is dependent of gender, age, ethnicity and genetic factors [6,19]. In diabetics RVD is also likely to be an early marker of retinopathy [7]. RVD may be a marker for complications of respiratory conditions beyond SDB. Chronic obstructive pulmonary disease (COPD) is amongst the top five global causes of morbidity and mortality. It is now increasingly recognized that cardiovascular complications, and not necessarily end-stage respiratory failure, are a major cause of morbidity and mortality in COPD patients. Further studies are needed to investigate whether RVD is an early indicator of cardiovascular risk in COPD and related pulmonary conditions. Finally, despite the interest that the study by Shankar et al. [9], may generate further work is required to explore the mechanisms and role of specific treatments in preventing and reversing the risk of cardiovascular disease in people with SDB [20]. A central question is whether treating sleep apnea decreases cardiovascular events in people with SDB. References [1] Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet 2009;373:82e93. [2] Gottlieb DJ, Yenokyan G, Newman AB, et al. Prospective study of obstructive sleep apnea and incident coronary heart disease and heart failure: the sleep heart health study. Circulation; 122: 352e60. [3] 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; 182: 269e77. [4] Di Murro A, Petramala L, Cotesta D, et al. Renin-angiotensin-aldosterone system in patients with sleep apnoea: prevalence of primary aldosteronism. J Renin Angiotensin Aldosterone Syst; 11: 165e72. [5] Monahan K, Redline S. Role of obstructive sleep apnea in cardiovascular disease. Curr Opin Cardiol; 26: 541e7. [6] Sun C, Wang JJ, Mackey DA, Wong TY. Retinal vascular caliber: systemic, environmental, and genetic associations. Surv Ophthalmol 2009;54: 74e95. [7] Nguyen TT, Wang JJ, Islam FM, et al. Retinal arteriolar narrowing predicts incidence of diabetes: the Australian diabetes, obesity and lifestyle (AusDiab) study. Diabetes 2008;57:536e9. [8] Wang JJ, Liew G, Klein R, et al. Retinal vessel diameter and cardiovascular mortality: pooled data analysis from two older populations. Eur Heart J 2007; 28:1984e92. [9] Shankar A, Peppard PE, Young T, et al. Sleep-disordered breathing and retinal microvascular diameter. Atherosclerosis 2013;226(1):122e6. [10] Boland LL, Shahar E, Wong TY, et al. Sleep-disordered breathing is not associated with the presence of retinal microvascular abnormalities: the sleep heart health study. Sleep 2004;27:467e73. [11] Liew G, Sharrett AR, Kronmal R, et al. Measurement of retinal vascular caliber: issues and alternatives to using the arteriole to venule ratio. Invest Ophthalmol Vis Sci 2007;48:52e7. [12] Brinchmann-Hansen O, Myhre K, Sandvik L. Retinal vessel responses to exercise and hypoxia before and after high altitude acclimatisation. Eye (Lond) 1989;3(Pt 6):768e76. [13] McQuillan LP, Leung GK, Marsden PA, Kostyk SK, Kourembanas S. Hypoxia inhibits expression of eNOS via transcriptional and posttranscriptional mechanisms. Am J Physiol 1994;267:H1921e7.
42
Y. Moodley, G.F. Watts / Atherosclerosis 226 (2013) 40e42
[14] Wang P, Zweier JL. Measurement of nitric oxide and peroxynitrite generation in the postischemic heart. Evidence for peroxynitrite-mediated reperfusion injury. J Biol Chem 1996;271:29223e30. [15] Peng Y, Yuan G, Overholt JL, Kumar GK, Prabhakar NR. Systemic and cellular responses to intermittent hypoxia: evidence for oxidative stress and mitochondrial dysfunction. Adv Exp Med Biol 2003;536:559e64. [16] Grimpen F, Kanne P, Schulz E, Hagenah G, Hasenfuss G, Andreas S. Endothelin1 plasma levels are not elevated in patients with obstructive sleep apnoea. Eur Respir J 2000;15:320e5. [17] Issa FG, Porostocky S, Feroah T. Effect of sleep and sighing on upper airway resistance in mongrel dogs. J Appl Physiol 1994;77:856e61.
[18] Drager LF, Jun J, Polotsky VY. Obstructive sleep apnea and dyslipidemia: implications for atherosclerosis. Curr Opin Endocrinol Diabetes Obes; 17: 161e5. [19] McGeechan K, Liew G, Macaskill P, et al. Meta-analysis: retinal vessel caliber and risk for coronary heart disease. Ann Intern Med 2009;151:404e13. [20] Somers VK, White DP, Amin R, et al. Sleep apnea and cardiovascular disease: an American heart association/American college of cardiology foundation scientific statement from the American heart association council for high blood pressure research professional education committee, council on clinical cardiology, stroke council, and council on cardiovascular nursing. In collaboration with the national heart, lung, and blood institute national center on sleep disorders research (national institutes of health). Circulation 2008;118:1080e111.