Sympathetic dysfunction in vasovagal syncope and the postural orthostatic tachycardia syndrome

Elisabeth Lambert, Gavin W Lambert, Elisabeth Lambert, Gavin W Lambert

Abstract

Orthostatic intolerance is the inability to tolerate the upright posture and is relieved by recumbence. It most commonly affects young women and has a major impact on quality of life and psychosocial well-being. Several forms of orthostatic intolerance have been described. The most common one is the recurrent vasovagal syncope (VVS) phenotype which presents as a transient and abrupt loss of consciousness and postural tone that is followed by rapid recovery. Another common type of orthostatic intolerance is the postural orthostatic tachycardia syndrome (POTS) which is characterized by an excessive rise in heart rate upon standing and is associated with symptoms of presyncope such as light-headedness, fatigue, palpitations, and nausea. Maintenance of arterial pressure under condition of reduced central blood volume during the orthostasis is accomplished in large part through sympathetic efferent nerve traffic to the peripheral vasculature. Therefore sympathetic nervous system (SNS) dysfunction is high on the list of possible contributors to the pathophysiology of orthostatic intolerance. Investigations into the role of the SNS in orthostatic intolerance have yielded mixed results. This review outlines the current knowledge of the function of the SNS in both VVS and POTS.

Keywords: orthostatic response; postural tachycardia; sympathetic nervous activity; syncope; tilt table.

Figures

Figure 1
Figure 1
Examples of heart rate (HR), blood pressure (BP) and muscle sympathetic nerve activity (MSNA) during supine rest and 30 degree tilt in one healthy control (A), one patient with recurrent vasovagal syncope (B), and one patient with postural tachycardia syndrome (C). Adapted from Vaddadi et al. (2007).
Figure 2
Figure 2
Sympathetic nerve varicosity. Tyrosine hydroxylase (TH) catalyzes the rate limiting step in norepinephrine (NE) synthesis. NE is stored in vesicles within the sympathetic varicosity and released to effector sites such as arterioles and venules in response to muscle sympathetic nerve firing (MSNA). Norepinephrine transporter (NET) recaptures 60–95% of released NE, and, of this, 70–90% is returned to intraneuronal vesicular storage. Vesicular monoamine transporter (VMAT2) is responsible for translocating NE from the cytoplasm into storage vesicles and is specific for sympathetic nerves. Dynamins are ubiquitous GTPases that support vesicular budding and fusion. Adapted from Vaddadi et al. (2011).

References

    1. Abed H., Ball P. A., Wang L. X. (2012). Diagnosis and management of postural orthostatic tachycardia syndrome: a brief review. J. Geriatr. Cardiol. 9, 61–67 10.3724/SP.J.1263.2012.00061
    1. Alboni P., Brignole M., Menozzi C., Raviele A., Del Rosso A., Dinelli M., et al. (2004). Clinical spectrum of neurally mediated reflex syncopes. Europace 6, 55–62 10.1016/j.eupc.2003.09.003
    1. Batzel J. J., Goswami N., Lackner H. K., Roessler A., Bachar M., Kappel F., et al. (2009). Patterns of cardiovascular control during repeated tests of orthostatic loading. Cardiovasc. Eng. 9, 134–143 10.1007/s10558-009-9086-z
    1. Bayles R., Baker E., Eikelis N., El-Osta A., Lambert G. (2010). Histone modifications regulate the norepinephrine transporter gene. Cell Cycle 9, 4600–4601 10.4161/cc.9.22.13888
    1. Bayles R., Baker E. K., Jowett J. B., Barton D., Esler M., El-Osta A., et al. (2013). Methylation of the SLC6a2 gene promoter in major depression and panic disorder. PLoS ONE 8:e83223 10.1371/journal.pone.0083223
    1. Bayles R., Harikrishnan K. N., Lambert E., Baker E. K., Agrotis A., Guo L., et al. (2012). Epigenetic modification of the norepinephrine transporter gene in postural tachycardia syndrome. Arterioscler. Thromb. Vasc. Biol. 32, 1910–1916 10.1161/ATVBAHA.111.244343
    1. Beacher F. D., Gray M. A., Mathias C. J., Critchley H. D. (2009). Vulnerability to simple faints is predicted by regional differences in brain anatomy. Neuroimage 47, 937–945 10.1016/j.neuroimage.2009.05.038
    1. Bechir M., Binggeli C., Corti R., Chenevard R., Spieker L., Ruschitzka F., et al. (2003). Dysfunctional baroreflex regulation of sympathetic nerve activity in patients with vasovagal syncope. Circulation 107, 1620–1625 10.1161/01.CIR.0000056105.87040.2B
    1. Benarroch E. E. (2012). Postural tachycardia syndrome: a heterogeneous and multifactorial disorder. Mayo Clin. Proc. 87, 1214–1225 10.1016/j.mayocp.2012.08.013
    1. Brignole M., Alboni P., Benditt D., Bergfeldt L., Blanc J. J., Bloch Thomsen P. E., et al. (2001). Guidelines on management (diagnosis and treatment) of syncope. Eur. Heart J. 22, 1256–1306 10.1053/euhj.2001.2739
    1. Calkins H., Dp Z. (2008). Hypotension and syncope, in Braunwald's Heart Disease, 8th Edn., eds Libby P., Bonow R. O., Mann D. L., Zipes D. P. (Philadelphia, PA: Saunders; ), 975–983
    1. Chapleau M. W., Cunningham J. T., Sullivan M. J., Wachtel R. E., Abboud F. M. (1995). Structural versus functional modulation of the arterial baroreflex. Hypertension 26, 341–347 10.1161/01.HYP.26.2.341
    1. Colman N., Nahm K., Ganzeboom K. S., Shen W. K., Reitsma J., Linzer M., et al. (2004). Epidemiology of reflex syncope. Clin. Auton. Res. 1, 9–17 10.1007/s10286-004-1003-3
    1. Convertino V. A. (2001). Lower body negative pressure as a tool for research in aerospace physiology and military medicine. J. Gravit. Physiol. 8, 1–14
    1. Cooke W. H., Rickards C. A., Ryan K. L., Kuusela T. A., Convertino V. A. (2009). Muscle sympathetic nerve activity during intense lower body negative pressure to presyncope in humans. J. Physiol. 587, 4987–4999 10.1113/jphysiol.2009.177352
    1. Eisenhofer G., Kopin I. J., Goldstein D. S. (2004). Catecholamine metabolism: a contemporary view with implications for physiology and medicine. Pharmacol. Rev. 56, 331–349 10.1124/pr.56.3.1
    1. Eisenhofer G., Smolich J. J., Cox H. S., Esler M. D. (1991). Neuronal reuptake of norepinephrine and production of dihydroxyphenylglycol by cardiac sympathetic nerves in the anesthetized dog. Circulation 84, 1354–1363 10.1161/01.CIR.84.3.1354
    1. Esler M., Alvarenga M., Pier C., Richards J., El-Osta A., Barton D., et al. (2006). The neuronal noradrenaline transporter, anxiety and cardiovascular disease. J. Psychopharmacol. 20, 60–66 10.1177/1359786806066055
    1. Fu Q., Verheyden B., Wieling W., Levine B. D. (2012). Cardiac output and sympathetic vasoconstrictor responses during upright tilt to presyncope in healthy humans. J. Physiol. 590, 1839–1848 10.1113/jphysiol.2011.224998
    1. Furlan R., Jacob G., Snell M., Robertson D., Porta A., Harris P., et al. (1998). Chronic orthostatic intolerance: a disorder with discordant cardiac and vascular sympathetic control. Circulation 98, 2154–2159 10.1161/01.CIR.98.20.2154
    1. Goldstein D. S., Eisenhofer G., Stull R., Folio C. J., Keiser H. R., Kopin I. J. (1988). Plasma dihydroxyphenylglycol and the intraneuronal disposition of norepinephrine in humans. J. Clin. Invest. 81, 213–220 10.1172/JCI113298
    1. Goldstein D. S., Holmes C., Frank S. M., Dendi R., Cannon R. O., 3rd, Sharabi Y., et al. (2002a). Cardiac sympathetic dysautonomia in chronic orthostatic intolerance syndromes. Circulation 106, 2358–2365 10.1161/01.CIR.0000036015.54619.B6
    1. Goldstein D. S., Robertson D., Esler M., Straus S. E., Eisenhofer G. (2002b). Dysautonomias: clinical disorders of the autonomic nervous system. Ann. Intern. Med. 137, 753–763 10.7326/0003-4819-137-9-200211050-00011
    1. Grubb B. P. (2008). Postural tachycardia syndrome. Circulation 117, 2814–2817 10.1161/CIRCULATIONAHA.107.761643
    1. Haensch C. A., Lerch H., Schlemmer H., Jigalin A., Isenmann S. (2010). Cardiac neurotransmission imaging with 123I-meta-iodobenzylguanidine in postural tachycardia syndrome. J. Neurol. Neurosurg. Psychiatr. 81, 339–343 10.1136/jnnp.2008.168484
    1. Haensch C. A., Tosch M., Katona I., Weis J., Isenmann S. (2014). Small-fiber neuropathy with cardiac denervation in postural tachycardia syndrome. Muscle Nerve. [Epub ahead of print]. 10.1002/mus.24245
    1. Hinghofer-Szalkay H., Konig E. M., Sauseng-Fellegger G., Zambo-Polz C. (1992). Biphasic blood volume changes with lower body suction in humans. Am. J. Physiol. 263, H1270–1275
    1. Hoffman B. B., Lefkowitz R., Taylor P. (1995). Neurotransmission: the autonomic and somatic motor nervous system, in Goodman and Gilman's The Pharmacological Basis of Therapeutics, ed Limbird JGHaLE. (New York, NY: McGraw Hill; ), 1105–1139
    1. Ivancsits S., Heider A., Rudiger H. W., Winker R. (2003). Orthostatic intolerance is not necessarily related to a specific mutation (Ala457Pro) in the human norepinephrine transporter gene. Am. J. Med. Sci. 325, 63–65 10.1097/00000441-200302000-00002
    1. Jacob G., Costa F., Shannon J. R., Robertson R. M., Wathen M., Stein M., et al. (2000). The neuropathic postural tachycardia syndrome. N. Engl. J. Med. 343, 1008–1014 10.1056/NEJM200010053431404
    1. Jacob G., Ertl A. C., Shannon J. R., Furlan R., Robertson R. M., Robertson D. (1998). Effect of standing on neurohumoral responses and plasma volume in healthy subjects. J. Appl. Physiol. 84, 914–921
    1. Jacob G., Shannon J. R., Costa F., Furlan R., Biaggioni I., Mosqueda-Garcia R., et al. (1999). Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance. Circulation 99, 1706–1712 10.1161/01.CIR.99.13.1706
    1. Jardine D. L., Ikram H., Frampton C. M., Frethey R., Bennett S. I., Crozier I. G. (1998). Autonomic control of vasovagal syncope. Am. J. Physiol. 274, H2110–2115
    1. Jardine D. L., Melton I. C., Crozier I. G., English S., Bennett S. I., Frampton C. M., et al. (2002). Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope. Am. J. Physiol. Heart Circ. Physiol. 282, H1804–H1809
    1. Jordan J., Shannon J. R., Diedrich A., Black B. K., Robertson D. (2002). Increased sympathetic activation in idiopathic orthostatic intolerance: role of systemic adrenoreceptor sensitivity. Hypertension 39, 173–178 10.1161/hy1201.097202
    1. Julu P. O., Cooper V. L., Hansen S., Hainsworth R. (2003). Cardiovascular regulation in the period preceding vasovagal syncope in conscious humans. J. Physiol. 549, 299–311 10.1113/jphysiol.2002.036715
    1. Kaufmann H. (1995). Neurally mediated syncope: pathogenesis, diagnosis, and treatment. Neurology 45, S12–S18
    1. Kim J. B., Suh S. I., Seo W. K., Koh S. B., Kim J. H. (2014). Right insular atrophy in neurocardiogenic syncope: a volumetric MRI study. AJNR Am. J. Neuroradiol. 35, 113–118 10.3174/ajnr.A3611
    1. Lambert E., Eikelis N., Esler M., Dawood T., Schlaich M., Bayles R., et al. (2008). Altered sympathetic nervous reactivity and norepinephrine transporter expression in patients with postural tachycardia syndrome. Circ. Arrhythm. Electrophysiol. 1, 103–109 10.1161/CIRCEP.107.750471
    1. Lipsitz L. A., Pluchino F. C., Wei J. Y., Rowe J. W. (1986). Syncope in institutionalized elderly: the impact of multiple pathological conditions and situational stress. J. Chronic Dis. 39, 619–630 10.1016/0021-9681(86)90187-6
    1. Liu J. E., Hahn R. T., Stein K. M., Markowitz S. M., Okin P. M., Devereux R. B., et al. (2000). Left ventricular geometry and function preceding neurally mediated syncope. Circulation 101, 777–783 10.1161/01.CIR.101.7.777
    1. Manolis A. S., Linzer M., Salem D., Estes N. A., 3rd (1990). Syncope: current diagnostic evaluation and management. Ann. Intern. Med. 112, 850–863 10.7326/0003-4819-112-11-850
    1. Mathias C. J., Deguchi K., Schatz I. (2001). Observations on recurrent syncope and presyncope in 641 patients. Lancet 357, 348–353 10.1016/S0140-6736(00)03642-4
    1. Medow M. S., Stewart J. M. (2007). The postural tachycardia syndrome. Cardiol. Rev. 15, 67–75 10.1097/01.crd.0000233768.68421.40
    1. Meredith I. T., Eisenhofer G., Lambert G. W., Jennings G. L., Thompson J., Esler M. D. (1992). Plasma norepinephrine responses to head-up tilt are misleading in autonomic failure. Hypertension 19, 628–633 10.1161/01.HYP.19.6.628
    1. Morillo C. A., Eckberg D. L., Ellenbogen K. A., Beightol L. A., Hoag J. B., Tahvanainen K. U., et al. (1997). Vagal and sympathetic mechanisms in patients with orthostatic vasovagal syncope. Circulation 96, 2509–2513 10.1161/01.CIR.96.8.2509
    1. Mosqueda-Garcia R., Furlan R., Fernandez-Violante R., Desai T., Snell M., Jarai Z., et al. (1997). Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J. Clin. Invest. 99, 2736–2744 10.1172/JCI119463
    1. Muenter Swift N., Charkoudian N., Dotson R. M., Suarez G. A., Low P. A. (2005). Baroreflex control of muscle sympathetic nerve activity in the postural orthostatic tachycardia syndrome. Am. J. Physiol. Heart Circ. Physiol. 289, H1226–H1233 10.1152/ajpheart.01243.2004
    1. Nagai M., Hoshide S., Kario K. (2010). The insular cortex and cardiovascular system: a new insight into the brain-heart axis. J. Am. Soc. Hypertens. 4, 174–182 10.1016/j.jash.2010.05.001
    1. Novak V., Honos G., Schondorf R. (1996). Is the heart “empty' at syncope? J. Auton. Nerv. Syst. 60, 83–92 10.1016/0165-1838(96)00040-9
    1. Nwazue V. C., Raj S. R. (2013). Confounders of vasovagal syncope: postural tachycardia syndrome. Cardiol. Clin. 31, 101–109 10.1016/j.ccl.2012.09.004
    1. Nwose E. U., Richards R. S., Cann N. G., Butkowski E. (2009). Cardiovascular risk assessment in prediabetes: A hypothesis. Med. Hypotheses 72, 271–275 10.1016/j.mehy.2008.07.063
    1. Okamoto L. E., Raj S. R., Peltier A., Gamboa A., Shibao C., Diedrich A., et al. (2012). Neurohumoral and haemodynamic profile in postural tachycardia and chronic fatigue syndromes. Clin. Sci. 122, 183–192
    1. Parry S. W., Kenny R. A. (1999). Tilt table testing in the diagnosis of unexplained syncope. QJM 92, 623–629 10.1093/qjmed/92.11.623
    1. Patwardhan A., Evans J., Bruce E., Knapp C. (2001). Heart rate variability during sympatho-excitatory challenges: comparison between spontaneous and metronomic breathing. Integr. Physiol. Behav. Sci. 36, 109–120 10.1007/BF02734045
    1. Protheroe C. L., Ravensbergen H. R. J. C., Inskip J. A., Claydon V. E. (2013). Tilt testing with combined lower body negative pressure: a “gold standard” for measuring orthostatic tolerance. J. Vis. Exp. e4315 10.3791/4315
    1. Rowell L. (1993). Human Cardiovascular Control. New York, NY: Oxford University Press
    1. Savage D. D., Corwin L., Mcgee D. L., Kannel W. B., Wolf P. A. (1985). Epidemiologic features of isolated syncope: the Framingham Study. Stroke 16, 626–629 10.1161/01.STR.16.4.626
    1. Schondorf R., Low P. A. (1993). Idiopathic postural orthostatic tachycardia syndrome: an attenuated form of acute pandysautonomia? Neurology 43, 132–137 10.1212/WNL.43.1_Part_1.132
    1. Schroeder C., Tank J., Boschmann M., Diedrich A., Sharma A. M., Biaggioni I., et al. (2002). Selective norepinephrine reuptake inhibition as a human model of orthostatic intolerance. Circulation 105, 347–353 10.1161/hc0302.102597
    1. Shannon J. R., Flattem N. L., Jordan J., Jacob G., Black B. K., Biaggioni I., et al. (2000). Orthostatic intolerance and tachycardia associated with norepinephrine-transporter deficiency. N. Engl. J. Med. 342, 541–549 10.1056/NEJM200002243420803
    1. Sheldon R. S., Sheldon A. G., Connolly S. J., Morillo C. A., Klingenheben T., Krahn A. D., et al. (2006). Age of first faint in patients with vasovagal syncope. J. Cardiovasc. Electrophysiol. 17, 49–54 10.1111/j.1540-8167.2005.00267.x
    1. Sneddon J. F., Counihan P. J., Bashir Y., Haywood G. A., Ward D. E., Camm A. J. (1993). Impaired immediate vasoconstrictor responses in patients with recurrent neurally mediated syncope. Am. J. Cardiol. 71, 72–76 10.1016/0002-9149(93)90713-M
    1. Stevens P. M. (1966). Cardiovascular dynamics during orthostasis and the influence of intravascular instrumentation. Am. J. Cardiol. 17, 211–218 10.1016/0002-9149(66)90354-7
    1. Stewart J. M. (2002). Pooling in chronic orthostatic intolerance: arterial vasoconstrictive but not venous compliance defects. Circulation 105, 2274–2281 10.1161/01.CIR.0000016348.55378.C4
    1. Streeten D. H., Anderson G. H., Jr., Richardson R., Thomas F. D. (1988). Abnormal orthostatic changes in blood pressure and heart rate in subjects with intact sympathetic nervous function: evidence for excessive venous pooling. J. Lab. Clin. Med. 111, 326–335
    1. Sun B. C., Emond J. A., Camargo C. A., Jr. (2004). Characteristics and admission patterns of patients presenting with syncope to U.S. emergency departments, 1992-2000. Acad. Emerg. Med. 11, 1029-1034
    1. Thieben M. J., Sandroni P., Sletten D. M., Benrud-Larson L. M., Fealey R. D., Vernino S., et al. (2007). Postural orthostatic tachycardia syndrome: the mayo clinic experience. Mayo Clin. Proc. 82, 308–313 10.1016/S0025-6196(11)61027-6
    1. Thoren P. (1979). Role of cardiac vagal C-fibers in cardiovascular control. Rev. Physiol. Biochem. Pharmacol. 86, 1–94 10.1007/BFb0031531
    1. Vaddadi G., Esler M. D., Dawood T., Lambert E. (2010). Persistence of muscle sympathetic nerve activity during vasovagal syncope. Eur. Heart J. 31, 2027–2033 10.1093/eurheartj/ehq071
    1. Vaddadi G., Guo L., Esler M., Socratous F., Schlaich M., Chopra R., et al. (2011). Recurrent postural vasovagal syncope: sympathetic nervous system phenotypes. Circ. Arrhythm. Electrophysiol. 4, 711–718 10.1161/CIRCEP.111.962332
    1. Vaddadi G., Lambert E., Corcoran S. J., Esler M. D. (2007). Postural syncope: mechanisms and management. Med. J. Aust. 187, 299–304 10.1002/9780470994801.ch13
    1. Van Dijk J. G. (2003). Fainting in animals. Clin. Auton. Res. 13, 247–255 10.1007/s10286-003-0099-1
    1. Van Lieshout J. J., Wieling W., Karemaker J. M., Eckberg D. L. (1991). The vasovagal response. Clin. Sci. 81, 575–586
    1. Vasquez E. C., Meyrelles S. S., Mauad H., Cabral A. M. (1997). Neural reflex regulation of arterial pressure in pathophysiological conditions: interplay among the baroreflex, the cardiopulmonary reflexes and the chemoreflex. Braz. J. Med. Biol. Res. 30, 521–532 10.1590/S0100-879X1997000400014
    1. Verheyden B., Liu J., Van Dijk N., Westerhof B. E., Reybrouck T., Aubert A. E., et al. (2008). Steep fall in cardiac output is main determinant of hypotension during drug-free and nitroglycerine-induced orthostatic vasovagal syncope. Heart Rhythm 5, 1695–1701 10.1016/j.hrthm.2008.09.003
    1. Victor R. G., Mark A. L. (1985). Interaction of cardiopulmonary and carotid baroreflex control of vascular resistance in humans. J. Clin. Invest. 76, 1592–1598 10.1172/JCI112142
    1. Wallin B. G., Sundlof G. (1982). Sympathetic outflow to muscles during vasovagal syncope. J. Auton. Nerv. Syst. 6, 287–291 10.1016/0165-1838(82)90001-7
    1. Ward C. R., Gray J. C., Gilroy J. J., Kenny R. A. (1998). Midodrine: a role in the management of neurocardiogenic syncope. Heart 79, 45–49

Source: PubMed

Sponsoren und Mitarbeiter

Krankheiten

Drogeninterventionen

3
Abonnieren