Causal associations between obstructive sleep apnea and cardiovascular diseases: a two-sample Mendelian randomized study_Chinese Journal of Evidence-Based Medicine

Authors：

LUO Binyu ¹ , XU Shihan ^1,2 , LI Yiwen ¹ , WANG Wenting ¹ , LIU Yanfei ^1,2 ,  HUANG Luqi ³ , LIU Yue ¹

1. National Clinical Research Center for Chinese Medicine Cardiology, Xiyuan Hospital, Chinese Academy of Chinese Medical Sciences, Beijing 100091, P. R. China;
2. The Second Department of Gerontology, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing 100091, P. R. China;
3. China Academy of Chinese Medical Sciences, Beijing 100078, P. R. China;

Corresponding author：

HUANG Luqi, Email: liuyue@188.com

Keywords：

Obstructive sleep apnea; Cardiovascular disease; Mendelian randomization; Heart failure; Hypertension

DOI：

10.7507/1672-2531.202303121

Video：

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Objective To analyze the causal relationship between obstructive sleep apnea (OSA) with its typical symptoms (daytime sleepiness and snoring) and cardiovascular diseases (hypertension, coronary heart disease, myocardial infarction, heart failure) by using Mendelian randomization. Methods We used the instrumental variables (IV) in the FINNGen database and the UK Biobank to perform two-sample Mendelian randomization (TSMR) analysis. The results of random-effects inverse variance weighting method (IVW) were the main results. MR-Egger method was used for pleiotropic analysis and sensitivity analysis was performed by the leave-one-out method to verify the reliability of the data. Results OSA could lead to hypertension (IVW β=0.043, 95%CI 0.012 to 0.074, P=0.006) and heart failure (IVW β=0.234, 95%CI 0.015 to 0.452, P=0.036). Daytime sleepiness also had a pathogenic effect on heart failure (IVW β=1.139, 95%CI 0.271 to 2.006, P=0.010). There was no causal association between OSA and CHD or MI, snoring and the four CVDs. There was no causal association between daytime sleepiness and hypertension, CHD or MI.Conclusion OSA and daytime sleepiness have pathogenic effects on hypertension and heart failure, with heart failure being the most affected.

Citation： LUO Binyu, XU Shihan, LI Yiwen, WANG Wenting, LIU Yanfei, HUANG Luqi, LIU Yue. Causal associations between obstructive sleep apnea and cardiovascular diseases: a two-sample Mendelian randomized study. Chinese Journal of Evidence-Based Medicine, 2023, 23(10): 1137-1142. doi: 10.7507/1672-2531.202303121 Copy

1.	Sharma S, Fox H, Aguilar F, et al. Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute heart failure with pulmonary hypertension and obstructive sleep apnea. The ASAP-HF pilot trial. Sleep, 2019, 42(7): zsz100.
2.	Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the american heart association. Circulation, 2016, 133(4): e38-e360..Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the american heart association. Circulation, 2016, 133(4): e38-e360.
3.	Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol, 2013, 177(9): 1006-1014.
4.	Drager LF, McEvoy RD, Barbe F, et al. Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Circulation, 2017, 136(19): 1840-1850.
5.	Floras JS. Sleep apnea and cardiovascular risk. J Cardiol, 2014, 63(1): 3-8.
6.	Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol, 2017, 69(7): 841-858.
7.	Chen L, Sun X, He Y, et al. Obstructive sleep apnea and atrial fibrillation: insights from a bidirectional Mendelian randomization study. BMC Med Genomics, 2022, 15(1): 28.
8.	Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
9.	Gabryelska A, Łukasik ZM, Makowska JS, et al. Obstructive sleep apnea: from intermittent hypoxia to cardiovascular complications via blood platelets. Front Neurol, 2018, 9: 635.
10.	Strausz S, Ruotsalainen S, Ollila HM, et al. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Eur Respir J, 2021, 57(5): 2003091.
11.	Haworth S, Mitchell R, Corbin L, et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat Commun, 2019, 10(1): 333.
12.	刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
13.	Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med, 2019, 7(8): 687-698.
14.	Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest, 2014, 146(5): 1387-1394.
15.	Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers, 2015, 1: 15015.
16.	Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: developed by the task force for cardiovascular disease prevention in clinical practice with representatives of the European society of cardiology and 12 medical societies with the special contribution of the European association of preventive cardiology (EAPC). Rev Esp Cardiol (Engl Ed), 2022, 75(5): 429.
17.	Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000, 342(19): 1378-1384.
18.	Iturriaga R, Del Rio R, Idiaquez J, et al. Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease. Biol Res, 2016, 49: 13.
19.	Serebrovskaya TV, Manukhina EB, Smith ML, et al. Intermittent hypoxia: cause of or therapy for systemic hypertension? Exp Biol Med (Maywood), 2008, 233(6): 627-650.
20.	Iturriaga R, Oyarce MP, Dias ACR. Role of carotid body in intermittent hypoxia-related hypertension. Curr Hypertens Rep, 2017, 19(5): 38.
21.	Del Rio R, Andrade DC, Lucero C, et al. Carotid body ablation abrogates hypertension and autonomic alterations induced by intermittent hypoxia in rats. Hypertension, 2016, 68(2): 436-445.
22.	Oldenburg O, Lamp B, Faber L, et al. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail, 2007, 9(3): 251-257.
23.	Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol, 2005, 45(12): 2008-2011.
24.	Tamisier R, Pépin JL, Rémy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J, 2011, 37(1): 119-128.
25.	Peng YJ, Yuan G, Ramakrishnan D, et al. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol, 2006, 577(Pt 2): 705-716.
26.	Luo B, Li Y, Zhu M, et al. Intermittent hypoxia and atherosclerosis: from molecular mechanisms to the therapeutic treatment. Oxid Med Cell Longev, 2022, 2022: 1438470.
27.	Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet, 2009, 373(9657): 82-93.
28.	Newman AB, Spiekerman CF, Enright P, et al. Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group. J Am Geriatr Soc, 2000, 48(2): 115-123.
29.	Gooneratne NS, Richards KC, Joffe M, et al. Sleep disordered breathing with excessive daytime sleepiness is a risk factor for mortality in older adults. Sleep, 2011, 34(4): 435-442.
30.	Kapur VK, Resnick HE, Gottlieb DJ. Sleep disordered breathing and hypertension: does self-reported sleepiness modify the association? Sleep, 2008, 31(8): 1127-1132.
31.	Ren R, Li Y, Zhang J, et al. Obstructive sleep apnea with objective daytime sleepiness is associated with hypertension. Hypertension, 2016, 68(5): 1264-1270.
32.	Chalegre ST, Lins-Filho OL, Lustosa TC, et al. Impact of CPAP on arterial stiffness in patients with obstructive sleep apnea: a meta-analysis of randomized trials. Sleep Breath, 2021, 25(3): 1195-1202.
33.	Oyama J, Yamamoto H, Maeda T, et al. 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(4): 231-236.
34.	McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med, 2016, 375(10): 919-931.
35.	Li Y, Miao Y, Zhang Q. Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study. Sleep, 2023, 46(3): zsac298.

1. Sharma S, Fox H, Aguilar F, et al. Auto positive airway pressure therapy reduces pulmonary pressures in adults admitted for acute heart failure with pulmonary hypertension and obstructive sleep apnea. The ASAP-HF pilot trial. Sleep, 2019, 42(7): zsz100.
2. Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the american heart association. Circulation, 2016, 133(4): e38-e360..Mozaffarian D, Benjamin EJ, Go AS, et al. Heart disease and stroke statistics-2016 update: a report from the american heart association. Circulation, 2016, 133(4): e38-e360.
3. Peppard PE, Young T, Barnet JH, et al. Increased prevalence of sleep-disordered breathing in adults. Am J Epidemiol, 2013, 177(9): 1006-1014.
4. Drager LF, McEvoy RD, Barbe F, et al. Sleep apnea and cardiovascular disease: lessons from recent trials and need for team science. Circulation, 2017, 136(19): 1840-1850.
5. Floras JS. Sleep apnea and cardiovascular risk. J Cardiol, 2014, 63(1): 3-8.
6. Javaheri S, Barbe F, Campos-Rodriguez F, et al. Sleep apnea: types, mechanisms, and clinical cardiovascular consequences. J Am Coll Cardiol, 2017, 69(7): 841-858.
7. Chen L, Sun X, He Y, et al. Obstructive sleep apnea and atrial fibrillation: insights from a bidirectional Mendelian randomization study. BMC Med Genomics, 2022, 15(1): 28.
8. Sekula P, Del Greco M F, Pattaro C, et al. Mendelian randomization as an approach to assess causality using observational data. J Am Soc Nephrol, 2016, 27(11): 3253-3265.
9. Gabryelska A, Łukasik ZM, Makowska JS, et al. Obstructive sleep apnea: from intermittent hypoxia to cardiovascular complications via blood platelets. Front Neurol, 2018, 9: 635.
10. Strausz S, Ruotsalainen S, Ollila HM, et al. Genetic analysis of obstructive sleep apnoea discovers a strong association with cardiometabolic health. Eur Respir J, 2021, 57(5): 2003091.
11. Haworth S, Mitchell R, Corbin L, et al. Apparent latent structure within the UK Biobank sample has implications for epidemiological analysis. Nat Commun, 2019, 10(1): 333.
12. 刘明, 高亚, 杨珂璐, 等. 孟德尔随机化研究的报告规范(STROBE-MR)解读. 中国循证医学杂志, 2022, 22(8): 978-987.
13. Benjafield AV, Ayas NT, Eastwood PR, et al. Estimation of the global prevalence and burden of obstructive sleep apnoea: a literature-based analysis. Lancet Respir Med, 2019, 7(8): 687-698.
14. Sateia MJ. International classification of sleep disorders-third edition: highlights and modifications. Chest, 2014, 146(5): 1387-1394.
15. Lévy P, Kohler M, McNicholas WT, et al. Obstructive sleep apnoea syndrome. Nat Rev Dis Primers, 2015, 1: 15015.
16. Visseren FLJ, Mach F, Smulders YM, et al. 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice: developed by the task force for cardiovascular disease prevention in clinical practice with representatives of the European society of cardiology and 12 medical societies with the special contribution of the European association of preventive cardiology (EAPC). Rev Esp Cardiol (Engl Ed), 2022, 75(5): 429.
17. Peppard PE, Young T, Palta M, et al. Prospective study of the association between sleep-disordered breathing and hypertension. N Engl J Med, 2000, 342(19): 1378-1384.
18. Iturriaga R, Del Rio R, Idiaquez J, et al. Carotid body chemoreceptors, sympathetic neural activation, and cardiometabolic disease. Biol Res, 2016, 49: 13.
19. Serebrovskaya TV, Manukhina EB, Smith ML, et al. Intermittent hypoxia: cause of or therapy for systemic hypertension? Exp Biol Med (Maywood), 2008, 233(6): 627-650.
20. Iturriaga R, Oyarce MP, Dias ACR. Role of carotid body in intermittent hypoxia-related hypertension. Curr Hypertens Rep, 2017, 19(5): 38.
21. Del Rio R, Andrade DC, Lucero C, et al. Carotid body ablation abrogates hypertension and autonomic alterations induced by intermittent hypoxia in rats. Hypertension, 2016, 68(2): 436-445.
22. Oldenburg O, Lamp B, Faber L, et al. Sleep-disordered breathing in patients with symptomatic heart failure: a contemporary study of prevalence in and characteristics of 700 patients. Eur J Heart Fail, 2007, 9(3): 251-257.
23. Usui K, Bradley TD, Spaak J, et al. Inhibition of awake sympathetic nerve activity of heart failure patients with obstructive sleep apnea by nocturnal continuous positive airway pressure. J Am Coll Cardiol, 2005, 45(12): 2008-2011.
24. Tamisier R, Pépin JL, Rémy J, et al. 14 nights of intermittent hypoxia elevate daytime blood pressure and sympathetic activity in healthy humans. Eur Respir J, 2011, 37(1): 119-128.
25. Peng YJ, Yuan G, Ramakrishnan D, et al. Heterozygous HIF-1alpha deficiency impairs carotid body-mediated systemic responses and reactive oxygen species generation in mice exposed to intermittent hypoxia. J Physiol, 2006, 577(Pt 2): 705-716.
26. Luo B, Li Y, Zhu M, et al. Intermittent hypoxia and atherosclerosis: from molecular mechanisms to the therapeutic treatment. Oxid Med Cell Longev, 2022, 2022: 1438470.
27. Bradley TD, Floras JS. Obstructive sleep apnoea and its cardiovascular consequences. Lancet, 2009, 373(9657): 82-93.
28. Newman AB, Spiekerman CF, Enright P, et al. Daytime sleepiness predicts mortality and cardiovascular disease in older adults. The Cardiovascular Health Study Research Group. J Am Geriatr Soc, 2000, 48(2): 115-123.
29. Gooneratne NS, Richards KC, Joffe M, et al. Sleep disordered breathing with excessive daytime sleepiness is a risk factor for mortality in older adults. Sleep, 2011, 34(4): 435-442.
30. Kapur VK, Resnick HE, Gottlieb DJ. Sleep disordered breathing and hypertension: does self-reported sleepiness modify the association? Sleep, 2008, 31(8): 1127-1132.
31. Ren R, Li Y, Zhang J, et al. Obstructive sleep apnea with objective daytime sleepiness is associated with hypertension. Hypertension, 2016, 68(5): 1264-1270.
32. Chalegre ST, Lins-Filho OL, Lustosa TC, et al. Impact of CPAP on arterial stiffness in patients with obstructive sleep apnea: a meta-analysis of randomized trials. Sleep Breath, 2021, 25(3): 1195-1202.
33. Oyama J, Yamamoto H, Maeda T, et al. 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(4): 231-236.
34. McEvoy RD, Antic NA, Heeley E, et al. CPAP for prevention of cardiovascular events in obstructive sleep apnea. N Engl J Med, 2016, 375(10): 919-931.
35. Li Y, Miao Y, Zhang Q. Causal associations of obstructive sleep apnea with cardiovascular disease: a Mendelian randomization study. Sleep, 2023, 46(3): zsac298.

Chinese Journal of Evidence-Based Medicine

Causal associations between obstructive sleep apnea and cardiovascular diseases: a two-sample Mendelian randomized study

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