title: Chemoreflexes, sleep apnea, and sympathetic dysregulation.
abstract: Obstructive sleep apnea (OSA) and hypertension are closely linked conditions. Disordered breathing events in OSA are characterized by increasing efforts against an occluded airway while asleep, resulting in a marked sympathetic response. This is predominantly due to hypoxemia activating the chemoreflexes, resulting in reflex increases in sympathetic neural outflow. In addition, apnea - and the consequent lack of inhibition of the sympathetic system that occurs with lung inflation during normal breathing - potentiates central sympathetic outflow. Sympathetic activation persists into the daytime, and is thought to contribute to hypertension and other adverse cardiovascular outcomes. This review discusses chemoreflex physiology and sympathetic modulation during normal sleep, as well as the sympathetic dysregulation seen in OSA, its extension into wakefulness, and changes after treatment. Evidence supporting the role of the peripheral chemoreflex in the sympathetic dysregulation seen in OSA, including in the context of comorbid obesity, metabolic syndrome, and systemic hypertension, is reviewed. Finally, alterations in cardiovascular variability and other potential mechanisms that may play a role in the autonomic imbalance in OSA are also discussed.
authors.affiliation: Sleep Medicine, Affiliated Communities Medical Center, 101 Willmar Avenue SW, Willmar, MN, USA, meghnapm@gmail.com.
authors.forename: Meghna P
authors.initials: MP
authors.lastname: Mansukhani
authors.forename: Tomas
authors.initials: T
authors.lastname: Kara
authors.forename: Sean M
authors.initials: SM
authors.lastname: Caples
authors.forename: Virend K
authors.initials: VK
authors.lastname: Somers
mesh_terms: D001342:Autonomic Nervous System Diseases / Q000209:etiology* / Q000503:physiopathology; D001794:Blood Pressure / Q000502:physiology*; D002628:Chemoreceptor Cells / Q000502:physiology*; D006801:Humans; D012018:Reflex / Q000502:physiology*; D012890:Sleep; D020181:Sleep Apnea, Obstructive / Q000150:complications / Q000503:physiopathology*; D013564:Sympathetic Nervous System / Q000503:physiopathology*
references.citation: N Engl J Med. 2000 May 11;342(19):1378-84
references.pmid: 10805822
references.citation: Eur Respir J. 2006 Jun;27(6):1229-35
references.pmid: 16455835
references.citation: J Physiol. 2009 Jul 1;587(Pt 13):3287-99
references.pmid: 19417094
references.citation: Exp Physiol. 2007 Jan;92(1):21-6
references.pmid: 17124275
references.citation: J Physiol. 1978 Jan;274:621-37
references.pmid: 625012
references.citation: Lancet Respir Med. 2013 Mar;1(1):61-72
references.pmid: 24321805
references.citation: Eur Respir J. 2010 Jul;36(1):143-50
references.pmid: 19996187
references.citation: J Appl Physiol (1985). 2010 Apr;108(4):906-12
references.pmid: 20150566
references.citation: Am J Respir Crit Care Med. 2001 Jan;163(1):19-25
references.pmid: 11208620
references.citation: Am J Respir Crit Care Med. 1996 Apr;153(4 Pt 1):1333-8
references.pmid: 8616563
references.citation: Hypertension. 2005 Aug;46(2):321-5
references.pmid: 15983234
references.citation: Circulation. 1998 Mar 17;97(10):943-5
references.pmid: 9529260
references.citation: Chest. 1993 Jun;103(6):1763-8
references.pmid: 8404098
references.citation: Hypertension. 2011 Mar;57(3):377-8
references.pmid: 21263122
references.citation: Sleep. 2013 Apr 01;36(4):547-53
references.pmid: 23565000
references.citation: J Pathol. 1982 Aug;137(4):287-304
references.pmid: 7097402
references.citation: Sleep. 1999 Jun 15;22(4):443-51
references.pmid: 10389220
references.citation: J Appl Physiol (1985). 1995 Jul;79(1):151-62
references.pmid: 7559214
references.citation: Exp Physiol. 2007 Jan;92(1):87-97
references.pmid: 17138622
references.citation: J Appl Physiol (1985). 2004 Nov;97(5):2020-5
references.pmid: 15258129
references.citation: Proc Soc Exp Biol Med. 1975 Jan;148(1):198-202
references.pmid: 236568
references.citation: Proc Natl Acad Sci U S A. 2003 Aug 19;100(17):10073-8
references.pmid: 12907705
references.citation: Auton Neurosci. 2010 Apr 19;154(1-2):42-7
references.pmid: 19926535
references.citation: Am J Respir Crit Care Med. 2006 Apr 15;173(8):910-6
references.pmid: 16424443
references.citation: J Neurosci. 2001 Jul 15;21(14):5381-8
references.pmid: 11438615
references.citation: Circulation. 1998 Sep 15;98(11):1071-7
references.pmid: 9736593
references.citation: Circulation. 1999 Mar 9;99(9):1183-9
references.pmid: 10069786
references.citation: Am J Cardiol. 1979 Oct 22;44(5):903-11
references.pmid: 386772
references.citation: Chest. 2000 May;117(5):1417-25
references.pmid: 10807831
references.citation: J Appl Physiol (1985). 2004 Feb;96(2):754-61
references.pmid: 14555683
references.citation: Handb Clin Neurol. 2011;98:471-87
references.pmid: 21056206
references.citation: J Appl Physiol (1985). 1997 Apr;82(4):1071-8
references.pmid: 9104841
references.citation: Eur Respir J. 1995 Feb;8(2):222-9
references.pmid: 7758555
references.citation: Brain Res. 1999 Jan 23;816(2):638-45
references.pmid: 9878890
references.citation: Am J Respir Crit Care Med. 2001 Feb;163(2):344-8
references.pmid: 11179104
references.citation: Crit Rev Biomed Eng. 2012;40(4):265-78
references.pmid: 23140119
references.citation: Sleep. 1996 Dec;19(10 Suppl):S206-9
references.pmid: 9085512
references.citation: J Am Coll Cardiol. 2008 Aug 19;52(8):686-717
references.pmid: 18702977
references.citation: J Hypertens. 2000 May;18(5):587-93
references.pmid: 10826562
references.citation: Am J Physiol. 1975 Aug;229(2):303-8
references.pmid: 240279
references.citation: Clin Cardiol. 1998 Apr;21(4):271-6
references.pmid: 9562937
references.citation: Am J Cardiol. 2012 Jan 1;109(1):140-5
references.pmid: 21945139
references.citation: Lancet. 2005 Mar 19-25;365(9464):1046-53
references.pmid: 15781100
references.citation: Curr Hypertens Rep. 2011 Jun;13(3):229-36
references.pmid: 21445721
references.citation: Exp Physiol. 2007 Mar;92(2):391-8
references.pmid: 17204492
references.citation: Respir Physiol Neurobiol. 2010 Apr 15;171(1):36-45
references.pmid: 20153844
references.citation: J Appl Physiol (1985). 1995 Jul;79(1):205-13
references.pmid: 7559221
references.citation: Exp Physiol. 2009 Sep;94(9):972-83
references.pmid: 19578126
references.citation: Angiology. 2014 Feb;65(2):98-103
references.pmid: 23427278
references.citation: Sleep. 2013 Jan 01;36(1):41-9
references.pmid: 23288970
references.citation: Circulation. 1998 Aug 25;98(8):772-6
references.pmid: 9727547
references.citation: N Engl J Med. 1993 Feb 4;328(5):303-7
references.pmid: 8419815
references.citation: Respir Physiol Neurobiol. 2004 Jul 20;141(2):145-55
references.pmid: 15239965
references.citation: Respir Physiol Neurobiol. 2010 Dec 31;174(3):230-4
references.pmid: 20804864
references.citation: J Clin Sleep Med. 2012 Oct 15;8(5):587-96
references.pmid: 23066375
references.citation: Am J Physiol. 1989 Dec;257(6 Pt 2):R1282-302
references.pmid: 2532478
references.citation: Sleep Breath. 2012 Jun;16(2):283-94
references.pmid: 21479903
references.citation: Am J Cardiol. 1987 Feb 1;59(4):256-62
references.pmid: 3812275
references.citation: Histochem Cell Biol. 2012 Mar;137(3):303-17
references.pmid: 22187044
references.citation: Hypertension. 2014 Feb;63(2):203-9
references.pmid: 24379177
references.citation: Prog Cardiovasc Dis. 2009 Jan-Feb;51(4):324-38
references.pmid: 19110134
references.citation: Chest. 2013 Sep;144(3):896-902
references.pmid: 23702567
references.citation: J Hypertens. 1997 Nov;15(11):1227-33
references.pmid: 9383171
references.citation: Chest. 1993 Mar;103(3):722-7
references.pmid: 8449058
references.citation: Auton Neurosci. 2013 Oct;177(2):148-53
references.pmid: 23622813
references.citation: Exp Physiol. 2007 Jan;92(1):51-65
references.pmid: 17124276
references.citation: Am J Physiol Regul Integr Comp Physiol. 2008 Oct;295(4):R1168-74
references.pmid: 18667715
references.citation: Hypertension. 1988 Jun;11(6 Pt 2):608-12
references.pmid: 3391673
references.citation: Physiol Rev. 2012 Jul;92(3):967-1003
references.pmid: 22811423
references.citation: Acta Otolaryngol. 1975 Mar-Apr;79(3-4):242-52
references.pmid: 1136764
references.citation: Am J Physiol Heart Circ Physiol. 2004 Nov;287(5):H2054-60
references.pmid: 15242836
references.citation: J Cell Physiol. 2011 Aug;226(8):1961-9
references.pmid: 21520047
references.citation: Auton Neurosci. 2013 Mar;174(1-2):8-14
references.pmid: 23305890
references.citation: Respir Physiol Neurobiol. 2010 Nov 30;174(1-2):135-45
references.pmid: 20837166
references.citation: Sheng Li Xue Bao. 2014 Feb 25;66(1):23-9
references.pmid: 24553866
references.citation: Circulation. 2005 Feb 8;111(5):614-21
references.pmid: 15699282
references.citation: Am J Respir Crit Care Med. 1996 Nov;154(5):1490-6
references.pmid: 8912770
references.citation: Circulation. 2000 Nov 21;102(21):2607-10
references.pmid: 11085964
references.citation: J Appl Physiol (1985). 1988 Oct;65(4):1548-52
references.pmid: 3182518
references.citation: J Gerontol A Biol Sci Med Sci. 2009 Feb;64(2):280-5
references.pmid: 19196901
references.citation: Chest. 2007 May;131(5):1406-13
references.pmid: 17494791
references.citation: J Appl Physiol (1985). 2012 Jul;113(2):232-6
references.pmid: 22539169
references.citation: Am J Respir Crit Care Med. 2005 Dec 1;172(11):1447-51
references.pmid: 16141444
references.citation: Hypertension. 2011 Nov;58(5):811-7
references.pmid: 21968750
references.citation: J Appl Physiol (1985). 2000 Oct;89(4):1333-9
references.pmid: 11007566
references.citation: Sleep. 1980;3(3-4):251-67
references.pmid: 7221335
references.citation: Acta Physiol Pol. 1985 Jan-Feb;36(1):76-82
references.pmid: 3834757
references.citation: JAMA. 2012 May 23;307(20):2161-8
references.pmid: 22618923
references.citation: Anat Rec (Hoboken). 2012 Sep;295(9):1385-95
references.pmid: 22851218
references.citation: Exp Physiol. 2007 Jan;92(1):79-85
references.pmid: 17085676
references.citation: J Hypertens. 1993 Jun;11(6):647-55
references.pmid: 8397244
references.citation: Am J Respir Crit Care Med. 2013 Apr 15;187(8):879-87
references.pmid: 23413266
references.citation: Am J Physiol Heart Circ Physiol. 2014 Feb;306(3):H309-16
references.pmid: 24322616
references.citation: Am J Physiol Regul Integr Comp Physiol. 2007 Jun;292(6):R2259-65
references.pmid: 17332161
references.citation: Hypertension. 2012 Jul;60(1):106-13
references.pmid: 22689747
references.citation: Am J Respir Crit Care Med. 2002 Aug 1;166(3):279-86
references.pmid: 12153958
references.citation: Physiol Rev. 2010 Jan;90(1):47-112
references.pmid: 20086074
references.citation: J Physiol. 2009 Jan 15;587(2):461-75
references.pmid: 19047207
references.citation: J Clin Invest. 1997 Jan 1;99(1):106-9
references.pmid: 9011563
references.citation: Can J Physiol Pharmacol. 2002 Dec;80(12):1136-44
references.pmid: 12564639
references.citation: Hypertension. 2011 Mar;57(3):549-55
references.pmid: 21242462
references.citation: Am J Epidemiol. 2013 May 1;177(9):1006-14
references.pmid: 23589584
references.citation: Brain Res. 1974 Mar 22;68(2):215-25
references.pmid: 4826896
references.citation: Brain Res. 2010 Sep 10;1351:141-149
references.pmid: 20621069
references.citation: Semin Respir Crit Care Med. 2005 Feb;26(1):25-32
references.pmid: 16052415
references.citation: BMC Pulm Med. 2013 Mar 13;13:13
references.pmid: 23497046
references.citation: J Clin Invest. 1974 May;53(5):1226-36
references.pmid: 4825222
references.citation: Am Rev Respir Dis. 1978 May;117(5):903-9
references.pmid: 655494
references.citation: Sleep. 2006 Mar;29(3):375-80
references.pmid: 16553024
references.citation: J Appl Physiol (1985). 1989 Nov;67(5):2095-100
references.pmid: 2513315
references.citation: J Appl Physiol (1985). 1990 Dec;69(6):2143-8
references.pmid: 2077012
references.citation: Respir Physiol Neurobiol. 2010 Dec 31;174(3):292-8
references.pmid: 20736087
references.citation: Circ Res. 1970 Aug;27(2):259-76
references.pmid: 5455628
references.citation: Acta Physiol Scand. 2003 Mar;177(3):377-84
references.pmid: 12609009
references.citation: Am J Cardiol. 2013 Jun 1;111(11):1650-4
references.pmid: 23578347
references.citation: N Engl J Med. 2011 Dec 15;365(24):2277-86
references.pmid: 22168642
references.citation: J Am Coll Cardiol. 1997 Oct;30(4):1009-14
references.pmid: 9316532
references.citation: J Clin Invest. 1991 Jun;87(6):1953-7
references.pmid: 2040688
references.citation: J Hypertens. 1997 Dec;15(12 Pt 2):1593-603
references.pmid: 9488210
references.citation: Auton Neurosci. 2010 Aug 25;156(1-2):138-43
references.pmid: 20627720
references.citation: J Clin Endocrinol Metab. 2012 Nov;97(11):4212-8
references.pmid: 22962427
references.citation: Lancet. 1979 Apr 7;1(8119):764-7
references.pmid: 86001
references.citation: Respir Physiol Neurobiol. 2010 Nov 30;174(1-2):29-36
references.pmid: 20416405
references.citation: Hypertension. 1992 Jun;19(6 Pt 1):555-61
references.pmid: 1592450
references.citation: Respir Physiol Neurobiol. 2010 Nov 30;174(1-2):156-61
references.pmid: 20804865
references.citation: J Appl Physiol (1985). 2001 Apr;90(4):1600-5
references.pmid: 11247966
references.citation: Circulation. 1999 Dec 7;100(23):2332-5
references.pmid: 10587337
references.citation: J Hypertens. 2011 Dec;29(12):2381-6
references.pmid: 21986622
references.citation: JAMA. 2013 Dec 11;310(22):2407-15
references.pmid: 24327037
references.citation: Biol Res. 2005;38(4):335-40
references.pmid: 16579514
references.citation: Respir Physiol Neurobiol. 2009 Apr 30;166(2):102-6
references.pmid: 19429526
references.citation: J Physiol. 2011 May 1;589(Pt 9):2401-14
references.pmid: 21486771
references.citation: Am J Physiol Regul Integr Comp Physiol. 2005 Apr;288(4):R856-62
references.pmid: 15793039
references.citation: J Physiol Sci. 2012 May;62(3):147-61
references.pmid: 22302247
references.citation: Chest. 2007 Feb;131(2):453-9
references.pmid: 17296647
references.citation: Histol Histopathol. 2008 Mar;23(3):271-80
references.pmid: 18072084
references.citation: J Hypertens. 1993 Oct;11(10):1133-7
references.pmid: 8258679
references.citation: Eur Respir J. 2012 Jun;39(6):1492-500
references.pmid: 22183481
references.citation: Hypertension. 2007 Aug;50(2):417-23
references.pmid: 17548722
references.citation: J Appl Physiol (1985). 2003 Oct;95(4):1394-404
references.pmid: 12819215
references.citation: Cardiovasc Res. 1982 Mar;16(3):163-72
references.pmid: 6805956
references.citation: Circulation. 1997 Oct 21;96(8):2586-94
references.pmid: 9355898
references.citation: Clin Physiol. 1999 Mar;19(2):127-34
references.pmid: 10200894
references.citation: Am J Physiol. 1982 Apr;242(4):H638-44
references.pmid: 7065276
references.citation: Hypertension. 2012 Jul;60(1):179-87
references.pmid: 22689746
references.citation: Curr Hypertens Rep. 2005 Jun;7(3):193-8
references.pmid: 15913493
references.citation: J Appl Physiol (1985). 1989 Nov;67(5):2101-6
references.pmid: 2513316
references.citation: Auton Neurosci. 2005 Aug 31;121(1-2):87-93
references.pmid: 15996901
references.citation: Am J Physiol. 1978 Mar;234(3):H293-9
references.pmid: 415620
references.citation: J Am Coll Cardiol. 2009 Nov 24;54(22):2075-83
references.pmid: 19926016
references.citation: Sleep. 1987 Feb;10(1):35-44
references.pmid: 3563246
references.citation: Am J Physiol Regul Integr Comp Physiol. 2011 Jul;301(1):R131-9
references.pmid: 21543638
references.citation: Med Hypotheses. 1981 Feb;7(2):127-31
references.pmid: 7219239
references.citation: Am J Respir Crit Care Med. 1997 Sep;156(3 Pt 1):886-94
references.pmid: 9310009
references.citation: JAMA. 2012 May 23;307(20):2169-76
references.pmid: 22618924
references.citation: J Physiol. 2010 Aug 15;588(Pt 16):3075-88
references.pmid: 20566662
references.citation: Chest. 2011 Dec;140(6):1503-1510
references.pmid: 21565964
references.citation: Blood Press Monit. 1997 Oct;2(5):229-235
references.pmid: 10234122
references.citation: J Physiol. 2001 Aug 1;534(Pt 3):881-90
references.pmid: 11483717
references.citation: Ann Intern Med. 2001 Jun 5;134(11):1015-23
references.pmid: 11388814
references.citation: J Physiol. 2008 Jul 1;586(13):3253-65
references.pmid: 18450774
references.citation: J Appl Physiol (1985). 1997 Jul;83(1):95-101
references.pmid: 9216950
references.citation: J Clin Invest. 1995 Oct;96(4):1897-904
references.pmid: 7560081
references.citation: Adv Exp Med Biol. 2010;669:271-4
references.pmid: 20217364
references.citation: Exp Physiol. 2007 Jan;92(1):45-50
references.pmid: 17099063
references.citation: J Appl Physiol (1985). 1985 Aug;59(2):384-91
references.pmid: 3928586
references.citation: Circulation. 2008 Sep 2;118(10):1080-111
references.pmid: 18725495
references.citation: J Hypertens. 2010 May;28(5):979-84
references.pmid: 20408258
references.citation: Exp Physiol. 2010 Jun;95(6):657-67
references.pmid: 20360424
references.citation: J Hum Hypertens. 2013 Jan;27(1):1-6
references.pmid: 22785050
references.citation: J Appl Physiol (1985). 1996 Mar;80(3):773-81
references.pmid: 8964736
references.citation: Drug Discov Today Dis Models. 2011 Winter;8(4):155-160
references.pmid: 22125570
references.citation: Sleep Breath. 2014 Mar;18(1):215-20
references.pmid: 23852444
references.citation: Arch Intern Med. 1997 Aug 11-25;157(15):1746-52
references.pmid: 9250236
references.citation: Hypertension. 2009 Apr;53(4):719-24
references.pmid: 19255361
references.citation: Neuroscience. 2008 Mar 3;152(1):189-97
references.pmid: 18207649
references.citation: J Physiol. 2008 Apr 15;586(8):2043-8
references.pmid: 18308822
references.citation: Lancet. 2002 Jan 19;359(9302):204-10
references.pmid: 11812555
references.citation: Qual Prim Care. 2012;20(4):287-98
references.pmid: 23113913
references.citation: Clin Physiol. 2000 May;20(3):234-41
references.pmid: 10792417
references.citation: Exp Biol Med (Maywood). 2013 Feb;238(2):223-32
references.pmid: 23404941
references.citation: J Auton Nerv Syst. 1996 Jan 5;56(3):184-90
references.pmid: 8847442