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Review article: Biomedical intelligence

Vol. 146 No. 4344 (2016)

Patent foramen ovale: a novel cardiovascular risk factor in patients with sleep disordered breathing and high altitude dwellers?

  • Emrush Rexhai
  • Urs Scherrer
  • Stefano F Rimoldi
Cite this as:
Swiss Med Wkly. 2016;146:w14371


Diseases associated with chronic hypoxaemia are a leading cause of morbidity and mortality in Western countries. Epidemiological data indicate that cardiovascular diseases contribute substantially to this problem, but the underlying mechanisms are incompletely understood. Sleep disordered breathing and high altitude exposure are frequent conditions associated with hypoxaemia. Recent evidence suggests that in these conditions the concomitant presence of a patent foramen ovale plays an important pathogenic role. For example, in patients with obstructive sleep apnoea the presence of a patent foramen ovale is associated with more severe sleep disordered breathing, nocturnal oxygen desaturation, generalised endothelial dysfunction and arterial hypertension. After patent foramen ovale closure, both sleep disordered breathing and cardiovascular phenotype improve, suggesting the existence of a possible causal link.

During short-term high altitude exposure, the presence of a patent foramen ovale, by aggravating altitude-induced hypoxaemia, facilitates exaggerated pulmonary hypertension. Interestingly, there is increasing evidence showing that in high-altitude dwellers a patent foramen ovale also alters the cardiovascular phenotype.

In this article we will summarise recent evidence demonstrating how a patent foramen ovale alters the cardiovascular phenotype and increases cardiovascular risk in patients with sleep disordered breathing and high-altitude dwellers.


  1. Heinzer R, Vat S, Marques-Vidal P, Marti-Soler H, Andries D, Tobback N, et al. Prevalence of sleep-disordered breathing in the general population: the HypnoLaus study. Lancet Respir Med. 2015;3(4):310–8. doi:
  2. Young T, Palta M, Dempsey J, Skatrud J, Weber S, Badr S. The occurrence of sleep-disordered breathing among middle-aged adults. N Engl J Med. 1993;328(17):1230–5. doi:
  3. Kessler R, Chaouat A, Weitzenblum E, Oswald M, Ehrhart M, Apprill M, et al. Pulmonary hypertension in the obstructive sleep apnoea syndrome: prevalence, causes and therapeutic consequences. Eur Respir J. 1996;9(4):787–94. doi:
  4. Stansbury RC, Strollo PJ. Clinical manifestations of sleep apnea. J Thorac Dis. 2015;7(9):E298–310.
  5. Bixler EO, Vgontzas AN, Ten Have T, Tyson K, Kales A. Effects of age on sleep apnea in men: I. Prevalence and severity. Am J Respir Crit Care Med. 1998;157(1):144–8. doi:
  6. Berry RB, Budhiraja R, Gottlieb DJ, Gozal D, Iber C, Kapur VK, et al.; American Academy of Sleep Medicine; Deliberations of the Sleep Apnea Definitions Task Force of the American Academy of Sleep Medicine. Rules for scoring respiratory events in sleep: update of the 2007 AASM Manual for the Scoring of Sleep and Associated Events. J Clin Sleep Med. 2012;8(5):597–619.
  7. Iber C, Ancoli-Israel S, Chesson ALJ, et al. The AASM manual for the scoring of sleep and associated events: rules, terminology and technical specifications. 1st ed Westchester, IL: American Academy of Sleep Medicine 2007.
  8. Tkacova R, Rankin F, Fitzgerald FS, Floras JS, Bradley TD. Effects of continuous positive airway pressure on obstructive sleep apnea and left ventricular afterload in patients with heart failure. Circulation. 1998;98(21):2269–75. doi:
  9. Somers VK, Dyken ME, Clary MP, Abboud FM. Sympathetic neural mechanisms in obstructive sleep apnea. J Clin Invest. 1995;96(4):1897–904. doi:
  10. Carpagnano GE, Kharitonov SA, Resta O, Foschino-Barbaro MP, Gramiccioni E, Barnes PJ. 8-Isoprostane, a marker of oxidative stress, is increased in exhaled breath condensate of patients with obstructive sleep apnea after night and is reduced by continuous positive airway pressure therapy. Chest. 2003;124(4):1386–92. doi:
  11. Yamauchi M, Nakano H, Maekawa J, Okamoto Y, Ohnishi Y, Suzuki T, et al. Oxidative stress in obstructive sleep apnea. Chest. 2005;127(5):1674–9. doi:
  12. Alonso-Fernández A, García-Río F, Arias MA, Hernanz A, de la Peña M, Piérola J, et al. Effects of CPAP on oxidative stress and nitrate efficiency in sleep apnoea: a randomised trial. Thorax. 2009;64(7):581–6. doi:
  13. Ryan S, Taylor CT, McNicholas WT. Selective activation of inflammatory pathways by intermittent hypoxia in obstructive sleep apnea syndrome. Circulation. 2005;112(17):2660–7. doi:
  14. Yokoe T, Minoguchi K, Matsuo H, Oda N, Minoguchi H, Yoshino G, et al. Elevated levels of C-reactive protein and interleukin-6 in patients with obstructive sleep apnea syndrome are decreased by nasal continuous positive airway pressure. Circulation. 2003;107(8):1129–34. doi:
  15. Rexhaj E, Rimoldi SF, Pratali L, Brenner R, Andries D, Soria R, et al. Sleep-Disordered Breathing and Vascular Function in Patients With Chronic Mountain Sickness and Healthy High-Altitude Dwellers. Chest. 2016;149(4):991–8. doi:
  16. Rimoldi SF, Ott S, Rexhaj E, de Marchi SF, Allemann Y, Gugger M, et al. Patent Foramen Ovale Closure in Obstructive Sleep Apnea Improves Blood Pressure and Cardiovascular Function. Hypertension. 2015;66(5):1050–7. doi:
  17. Bruno RM, Rossi L, Fabbrini M, Duranti E, Di Coscio E, Maestri M, et al. Renal vasodilating capacity and endothelial function are impaired in patients with obstructive sleep apnea syndrome and no traditional cardiovascular risk factors. J Hypertens. 2013;31(7):1456–64, discussion 1464. doi:
  18. Nadeem R, Harvey M, Singh M, Khan AA, Albustani M, Baessler A, et al. Patients with obstructive sleep apnea display increased carotid intima media: a meta-analysis. Int J Vasc Med. 2013;2013:839582.
  19. Nagahama H, Soejima M, Uenomachi H, Higashi Y, Yotsumoto K, Samukawa T, et al. Pulse wave velocity as an indicator of atherosclerosis in obstructive sleep apnea syndrome patients. Intern Med. 2004;43(3):184–8. doi:
  20. Weinreich G, Wessendorf TE, Erdmann T, Moebus S, Dragano N, Lehmann N, et al.; Heinz Nixdorf Recall (HNR) study group. Association of obstructive sleep apnoea with subclinical coronary atherosclerosis. Atherosclerosis. 2013;231(2):191–7. doi:
  21. 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(19):1378–84. doi:
  22. Rimoldi SF, Messerli FH, Bangalore S, Scherrer U. Resistant hypertension: what the cardiologist needs to know. Eur Heart J. 2015;36(40):2686–95. doi:
  23. Logan AG, Perlikowski SM, Mente A, Tisler A, Tkacova R, Niroumand M, et al. High prevalence of unrecognized sleep apnoea in drug-resistant hypertension. J Hypertens. 2001;19(12):2271–7. doi:
  24. Pedrosa RP, Drager LF, Gonzaga CC, Sousa MG, de Paula LK, Amaro AC, et al. Obstructive sleep apnea: the most common secondary cause of hypertension associated with resistant hypertension. Hypertension. 2011;58(5):811–7. doi:
  25. Rimoldi SF, Scherrer U, Messerli FH. Secondary arterial hypertension: when, who, and how to screen? Eur Heart J. 2014;35(19):1245–54. doi:
  26. Shahar E, Whitney CW, Redline S, Lee ET, Newman AB, Nieto FJ, et al. Sleep-disordered breathing and cardiovascular disease: cross-sectional results of the Sleep Heart Health Study. Am J Respir Crit Care Med. 2001;163(1):19–25. doi:
  27. Yaggi HK, Concato J, Kernan WN, Lichtman JH, Brass LM, Mohsenin V. Obstructive sleep apnea as a risk factor for stroke and death. N Engl J Med. 2005;353(19):2034–41. doi:
  28. Yumino D, Tsurumi Y, Takagi A, Suzuki K, Kasanuki H. Impact of obstructive sleep apnea on clinical and angiographic outcomes following percutaneous coronary intervention in patients with acute coronary syndrome. Am J Cardiol. 2007;99(1):26–30. doi:
  29. Arikawa T, Toyoda S, Haruyama A, Amano H, Inami S, Otani N, et al. Impact of Obstructive Sleep Apnoea on Heart Failure with Preserved Ejection Fraction. Heart Lung Circ. 2016;25(5):435–41. doi:
  30. Javaheri S, Blackwell T, Ancoli-Israel S, Ensrud KE, Stone KL, Redline S; Osteoporotic Fractures in Men Study Research Group. Sleep-disordered Breathing and Incident Heart Failure in Older Men. Am J Respir Crit Care Med. 2016;193(5):561–8. doi:
  31. Becker H, Brandenburg U, Peter JH, Von Wichert P. Reversal of sinus arrest and atrioventricular conduction block in patients with sleep apnea during nasal continuous positive airway pressure. Am J Respir Crit Care Med. 1995;151(1):215–8. doi:
  32. Mehra R, Benjamin EJ, Shahar E, Gottlieb DJ, Nawabit R, Kirchner HL, et al.; Sleep Heart Health Study. Association of nocturnal arrhythmias with sleep-disordered breathing: The Sleep Heart Health Study. Am J Respir Crit Care Med. 2006;173(8):910–6. doi:
  33. Ismail K, Roberts K, Manning P, Manley C, Hill NS. OSA and pulmonary hypertension: time for a new look. Chest. 2015;147(3):847–61. doi:
  34. Guyton AC, Lindsey AW, Abernathy B, Richardson T. Venous return at various right atrial pressures and the normal venous return curve. Am J Physiol. 1957;189(3):609–15.
  35. Buda AJ, Pinsky MR, Ingels NB, Jr, Daughters GT, 2nd, Stinson EB, Alderman EL. Effect of intrathoracic pressure on left ventricular performance. N Engl J Med. 1979;301(9):453–9. doi:
  36. Lattimore JD, Wilcox I, Adams MR, Kilian JG, Celermajer DS. Treatment of obstructive sleep apnoea leads to enhanced pulmonary vascular nitric oxide release. Int J Cardiol. 2008;126(2):229–33. doi:
  37. Rexhaj E, Bloch J, Jayet PY, Rimoldi SF, Dessen P, Mathieu C, et al. Fetal programming of pulmonary vascular dysfunction in mice: role of epigenetic mechanisms. Am J Physiol Heart Circ Physiol. 2011;301(1):H247–52. doi:
  38. Sajkov D, Wang T, Saunders NA, Bune AJ, Neill AM, Douglas Mcevoy R. Daytime pulmonary hemodynamics in patients with obstructive sleep apnea without lung disease. Am J Respir Crit Care Med. 1999;159(5 Pt 1):1518–26. doi:
  39. Hagen PT, Scholz DG, Edwards WD. Incidence and size of patent foramen ovale during the first 10 decades of life: an autopsy study of 965 normal hearts. Mayo Clin Proc. 1984;59(1):17–20. doi:
  40. Messerli FH, Rimoldi SF, Scherrer U, Meier B. Economy Class Syndrome, patent foramen ovale and stroke. Am J Cardiol. 2016;S0002-9149(16)31256-5.
  41. Allemann Y, Hutter D, Lipp E, Sartori C, Duplain H, Egli M, et al. Patent foramen ovale and high-altitude pulmonary edema. JAMA. 2006;296(24):2954–8. doi:
  42. Lau EM, Jaijee SK, Melehan KL, Wong KK, Yee BJ, Grunstein RR, et al. Prevalence of patent foramen ovale and its impact on oxygen desaturation in obstructive sleep apnea. Int J Cardiol. 2013;165(1):35–40. doi:
  43. Schwerzmann M, Seiler C, Lipp E, Guzman R, Lövblad KO, Kraus M, et al. Relation between directly detected patent foramen ovale and ischemic brain lesions in sport divers. Ann Intern Med. 2001;134(1):21–4. doi:
  44. Seiler C. Patent foramen ovale (PFO): is there life before death in the presence of PFO? Eur J Clin Invest. 2015;45(8):875–82. doi:
  45. Soliman OI, Geleijnse ML, Meijboom FJ, Nemes A, Kamp O, Nihoyannopoulos P, et al. The use of contrast echocardiography for the detection of cardiac shunts. Eur J Echocardiogr. 2007;8(3):S2–12. doi:
  46. Shanoudy H, Soliman A, Raggi P, Liu JW, Russell DC, Jarmukli NF. Prevalence of patent foramen ovale and its contribution to hypoxemia in patients with obstructive sleep apnea. Chest. 1998;113(1):91–6. doi:
  47. Beelke M, Angeli S, Del Sette M, Gandolfo C, Cabano ME, Canovaro P, et al. Prevalence of patent foramen ovale in subjects with obstructive sleep apnea: a transcranial Doppler ultrasound study. Sleep Med. 2003;4(3):219–23. doi:
  48. Kraiczi H, Caidahl K, Samuelsson A, Peker Y, Hedner J. Impairment of vascular endothelial function and left ventricular filling : association with the severity of apnea-induced hypoxemia during sleep. Chest. 2001;119(4):1085–91. doi:
  49. Rexhaj E, Rimoldi SF, Pratali L, Brenner R, Andries D, Soria R, et al. Sleep-Disordered Breathing and Vascular Function in Patients With Chronic Mountain Sickness and Healthy High-Altitude Dwellers. Chest. 2016;149(4):991–8. doi:
  50. Rimoldi SF, Ott SR, Rexhaj E, von Arx R, de Marchi SF, Brenner R, et al. Effect of patent foramen ovale closure on obstructive sleep apnea. J Am Coll Cardiol. 2015;65(20):2257–8. doi:
  51. Bailey DM, Rimoldi SF, Rexhaj E, Pratali L, Salinas Salmòn C, Villena M, et al. Oxidative-nitrosative stress and systemic vascular function in highlanders with and without exaggerated hypoxemia. Chest. 2013;143(2):444–51. doi:
  52. Rimoldi SF, Rexhaj E, Pratali L, Bailey DM, Hutter D, Faita F, et al. Systemic vascular dysfunction in patients with chronic mountain sickness. Chest. 2012;141(1):139–46. doi:
  53. Elliott JE, Laurie SS, Kern JP, Beasley KM, Goodman RD, Kayser B, et al. AltitudeOmics: impaired pulmonary gas exchange efficiency and blunted ventilatory acclimatization in humans with patent foramen ovale after 16 days at 5,260 m. J Appl Physiol (1985). 2015;118(9):1100–12.
  54. Brenner R, Pratali L, Rimoldi SF, Murillo Jauregui CX, Soria R, Rexhaj E, et al. Exaggerated pulmonary hypertension and right ventricular dysfunction in high-altitude dwellers with patent foramen ovale. Chest. 2015;147(4):1072–9. doi:
  55. Johansson MC, Eriksson P, Peker Y, Hedner J, Råstam L, Lindblad U. The influence of patent foramen ovale on oxygen desaturation in obstructive sleep apnoea. Eur Respir J. 2007;29(1):149–55. doi:
  56. Shaikh ZF, Jaye J, Ward N, Malhotra A, de Villa M, Polkey MI, et al. Patent foramen ovale in severe obstructive sleep apnea: clinical features and effects of closure. Chest. 2013;143(1):56–63. doi:
  57. Konecny T, Khanna AD, Novak J, Jama AA, Zawadowski GM, Orban M, et al. Interatrial pressure gradients during simulated obstructive sleep apnea: a catheter-based study. Catheter Cardiovasc Interv. 2014;84(7):1138–45. doi:
  58. Schäfer H, Hasper E, Ewig S, Koehler U, Latzelsberger J, Tasci S, et al. Pulmonary haemodynamics in obstructive sleep apnoea: time course and associated factors. Eur Respir J. 1998;12(3):679–84. doi:
  59. Soliman A, Shanoudy H, Liu J, Russell DC, Jarmukli NF. Increased prevalence of patent foramen ovale in patients with severe chronic obstructive pulmonary disease. J Am Soc Echocardiogr. 1999;12(2):99–105. doi:
  60. Xie A, Skatrud JB, Dempsey JA. Effect of hypoxia on the hypopnoeic and apnoeic threshold for CO(2) in sleeping humans. J Physiol. 2001;535(Pt 1):269–78. doi:
  61. Agnoletti G, Iserin L, Lafont A, Sidi D, Desnos M. Obstructive sleep apnoea and patent foramen ovale: successful treatment of symptoms by percutaneous foramen ovale closure. J Interv Cardiol. 2005;18(5):393–5. doi:
  62. Pinet C, Orehek J. CPAP suppression of awake right-to-left shunting through patent foramen ovale in a patient with obstructive sleep apnoea. Thorax. 2005;60(10):880–1. doi:
  63. Silver B, Greenbaum A, McCarthy S. Improvement in sleep apnea associated with closure of a patent foramen ovale. J Clin Sleep Med. 2007;3(3):295–6.

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