The Pathophysiology of Common Causes of Syncope

Home , Orthostatic syncope, Syncope (medicine)

750 Postgrad Med J 2000;76:750–753 Postgrad Med J: first published as 10.1136/pgmj.76.902.750 on 1 December 2000. Downloaded from The pathophysiology of common causes of syncope

W Arthur, G C Kaye

This is the first of three Syncope is a transient loss of consciousness experienced this symptom.6 As our under- papers on syncope; the secondary to inadequate cerebral perfusion standing of human neuroautonomic regulation second and third papers will be published in January with oxygenated blood. It is a common medical has evolved it has become apparent that the and February respectively. problem, accounting for around 5% of acute vasovagal episode, although the most common, medical admissions and 3% of emergency is one of a number of neurally mediated synco- 1 department visits. Syncope secondary to pal syndromes. cardiac causes carries the worst prognosis, with 2 a one year mortality rate of 20–30%. An Neurally mediated syncopal syndromes understanding of the events preceding syncope Neurally mediated syncope can be classified is essential if the correct diagnostic strategy is into several distinct syndromes (box 1). These to be implemented. are all associated with acute vasodilatation of the arterial and venous beds and relative or General pathophysiological concepts A state of consciousness is maintained by absolute bradycardia. All of the neurally medi- adequate cerebral blood flow. Cerebral vascular ated syncopal syndromes involve an inappro- autoregulation ensures that the cerebral blood priate reflex with aVerent, central, and eVerent 7 flow is kept within a narrow range, independent pathways. During tilt table testing, the triggers of the underlying systemic blood pressure. In a for vasovagal syncope are thought to arise from young healthy adult the systolic blood pressure the heart.8 As a result, the term “neurocardio- may fall to 70 mm Hg without significant cer- genic syncope” has been used to define one of ebral ischaemia.3 Elderly people and those with the commonest responses found during tilt chronic hypertension are susceptible to rela- testing (fig 1).9 tively small falls in systemic blood pressure, leading to an increased incidence of syncope in this population.4 The term “vasovagal” as applied to syncope has been used since the early 1900s and has become synonymous with the common Venous return “faint”.5 Early studies found that vasovagal syncope was the most common cause of faint- ing, being found in 58% of patients who had Left ventricular filling

Box 1: Neurally mediated reﬂex http://pmj.bmj.com/ syncopal syndromes

x Vasovagal (emotional, common) faint Sympathetic tone x Carotid sinus syncope x Neurocardiogenic syncope (head up tilt/gravitational syncope) Vigorous ventricular contraction in x Increased intrathoracic pressure underfilled chamber Cough syncope on September 29, 2021 by guest. Protected copyright. Sneeze syncope Trumpet player’s syncope Mechanoreceptor C fibre discharge Weight lifter’s syncope Mess Trick syncope Valsalva induced syncope

x Postmicturition syncope CNS x Gastrointestinal stimulation syncope Rectal examination Cardiology Defaecation syncope Department, Castle Gastrointestinal instrumentation Vasodilatation Bradycardia Hill Hospital, Castle x Oesophageal/nasopharyngeal stimulation Road, Cottingham, Swallow syncope East Yorkshire HU16 5JQ, UK Glossopharyngeal neuralgia W Arthur x Diving reﬂex GCKaye x Drug induced syncope Syncope Correspondence to: Glyceryl trinitrate Figure 1 Haemodynamic and autonomic changes Dr Arthur Isoprenaline characteristic of neurocardiogenic syncope. (Reproduced by [reproduced from reference 7, with permission from Advanstar Communications Inc, as Submitted 30 December reprinted from Neurology 1995;45(suppl 5):15. 1999 permission] Neurology® is a registered trademark of the American Accepted 16 February 2000 Academy of Neurology.)

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NEUROCARDIOGENIC SYNCOPE CAROTID SINUS HYPERSENSITIVITY AND CAROTID In order to maintain adequate cerebral blood SINUS SYNCOPE flow in the upright position, man has evolved a Pressure exerted on the internal carotid artery series of autonomic reflexes. On standing, 300 just above the bifurcation of the common to 800 ml of blood shift from the thorax to the carotid artery leads to slowing of the sinus rate lower extremities. This lowers the venous and impaired atrioventricular node conduc- return and hence the cardiac output. Normally tion. This is a normal response resulting from this leads to reduced stimulation of barorecep- stimulation of the carotid sinus. In carotid tors in the carotid sinus and aortic arch and sinus hypersensitivity this reflex is exaggerated mechanoreceptors (vagal C fibres) in the wall and is described in three forms: cardioinhibi- of the left ventricle. These receptors inhibit the tory, giving rise to asystole of three seconds or brain stem neurones responsible for sympa- more; vasodepressor, leading to a fall in systo- thetic stimulation; they also promote the lic blood pressure of 50 mm Hg or more; or the 13 neurones in charge of parasympathetic drive. response may be mixed. Studies have shown The end result is increased sympathetic tone that 5–25% of asymptomatic older men have 14 and maintenance of the blood pressure. carotid sinus hypersensitivity. At the same Conversely a rise in blood pressure or intravas- time only 5–20% of patients showing carotid sinus hypersensitivity actually have syncope of cular volume increases baroreceptor and mech- 14 anoreceptor output, which leads to sympa- carotid sinus origin. Diagnosis of carotid thetic withdrawal and parasympathetic sinus syncope requires that spontaneous symp- stimulation.10 toms of presyncope or syncope be reproduced It is thought that the mechanoreceptors in by carotid sinus massage. the left ventricle are not only innervated by Despite the fact that the cardioinhibitory stretch but also by vigorous and forceful systo- response is dominant, a vasodepressor component of the syndrome can be elicited by carotid lic contraction. In patients with neurocardio- sinus massage in the majority of patients with genic syncope, overzealous left ventricular con- carotid sinus syncope.15 The vasodepressor traction occurs in response to reduced venous reflex in these patients peaks at the end of return. Hence the aVerent signals from the left carotid sinus massage and may last for up to ventricle override the baroreceptor responses, two minutes. This is in contrast to the leading to an inappropriate decrease in sympa- cardioinhibitory response, in which the maxi- thetic tone and an increase in parasympathetic mum asystolic pause normally occurs within a (vagal) tone. Paradoxically the clinical picture few beats of the application of carotid sinus is one of sudden hypotension reflecting dimin- massage. ished sympathetic vasoconstrictor tone accom- panied by vagally induced inappropriate brady- Orthostatic syncope and dysautonomic cardia. disturbances of blood pressure control The other forms of neurally mediated Orthostatic syncope results from the venous syncope share with neurocardiogenic syncope a pooling of blood that occurs upon changing triggering event stimulating adrenergic tone, from a supine to an upright position. There is followed by a clinical prodrome of vagal no vagal hyperactivity associated with this http://pmj.bmj.com/ overactivation and then sympathetic with- venous pooling and this distinguishes orthos- drawal. In the case of the emotionally induced tatic syncope from neurocardiogenic syncope. vasovagal faint, higher cortical sites are the Orthostatic syncope may be the consequence predominant triggers of the aVerent limb of the of transient or chronic volume depletion or reflex arc, which result in increased sympa- abnormal vasomotor compensatory mecha- thetic nervous system stimulation. This is then nisms. Owing to a relative lack of intravascular followed by the presyncopal or aura phase volume, the patient’s blood pressure does not on September 29, 2021 by guest. Protected copyright. characterised by diaphoresis, epigastric dis- become suYciently increased regardless of the comfort, dizziness/vertigo, and nausea. These increase in heart rate. Actual or relative central prodromal symptoms are induced by the vascular volume depletion may occur because increased parasympathetic tone. They may last of gastrointestinal bleeding, dehydration, ex- anywhere from less than one second to several cessive diuresis, or the use of vasodilating minutes. These events proceed to syncope drugs. unless the subject lies supine or removes the Following change in posture to the upright triggering stimulus. The lack of warning signs position, baroreceptors provoke an increase in does not exclude the possibility of neurocardio- medullary sympathetic outflow. This leads to genic syncope; a “malignant” form has been vasoconstriction of the systemic resistance ves- described in which there is a rapid deteriora- sels and the splanchnic capacitance vessels. tion in the haemodynamic state.11 Compensation for continued orthostatic stress The haemodynamic responses evoked in depends principally on the arterial barorecep- neurally mediated syncope may be predomi- tors. Disorders of abnormal autonomic vaso- nantly vasodepressor, cardioinhibitory, or motor control leading to orthostatic hypoten- mixed. The mixed response is most common, sion may be primary or more commonly although the vasodepressor component of the secondary. Primary pure autonomic failure and mixed response appears to be the dominant multiple system atrophy are both characterised factor in up to 85% of aVected patients.12 In the by autonomic dysfunction, where the patient is malignant type of neurocardiogenic syncope unable to produce the appropriate vasomotor the cardioinhibitory component is pro- response following baroreceptor stimulation.16 nounced. Secondary autonomic disturbances leading to

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disturbance of blood pressure control include diabetic and alcoholic neuropathies, Addison’s Box 2: Possible causes of syncope in disease, paraneoplastic syndromes, and pro- aortic stenosis longed periods of physical inactivity. Those x Inadequate increase in cardiac output aVected by dysautonomic syncope may suVer and hence blood pressure maintenance the classical fall of blood pressure of 20 mm because of ﬁxed mechanical obstruction Hg within three minutes of standing or they x Arrhythmias may have a progressive decline in blood pressure over a protracted period of time.16 x Raised left ventricular systolic pressure Older patients are at particular risk of orthos- giving rise to mechanoreceptor tatic hypotension and syncope because of stimulation and hence neurally mediated altered baroreceptor responsiveness, poly- syncope pharmacy, and the increased risk of volume x Concurrent degenerative disease of the depletion. atrioventricular node and His bundle leading to bradyarrhythmias Cardiac syncope x Atrial tachyarrhythmias may Cardiac syncope results from inadequate eVec- substantially reduce ejection fraction in tive cardiac output and may reﬂect serious those with severe diastolic dysfunction underlying structural heart disease. A cardiac cause for syncope is an independent predictor of sudden death and mortality.2 The causes

may be electrical (arrhythmic) or mechanical 20 (obstructive). Patients with advanced heart sinus pause. Cardiac conduction system failure and syncope have a one year mortality of disease may represent acute or long standing 45%, compared with 12% in patients without cardiac ischaemia, cardiomyopathy, hyper- syncope.17 tension, valvar heart disease, or simply a chronic degenerative process. Persistent or epi- ARRHYTHMIC SYNCOPE sodic high grade atrioventicular block may Rhythm disturbances are among the most fre- result in suYcient loss of cardiac output to quent and potentially hazardous causes of syn- cause syncope. Severe bradycardia can leave cope and dizziness. Syncope from arrhythmia the patient susceptible to ventricular tachyar- most commonly results from ventricular tachy- rhythmias in association with a “pause depend- cardia, which accounts for 11% of all cases of ent” long QT interval.21 syncope.2 Those patients with depressed left ventricular function or myocardial ischaemia MECHANICAL OBSTRUCTION AND OTHER CAUSES with or without infarction are at particular risk Obstruction to blood flow from the left of ventricular tachycardia. The association of ventricular outflow tract classically brings ventricular tachycardia with a low left ventricu- about syncope on exertion. This heralds a poor lar ejection fraction cannot be overemphasised prognosis in severe aortic stenosis and warrants and must be considered in any patient with poor left ventricular function, whatever the urgent valve replacement. Aortic stenosis may http://pmj.bmj.com/ aetiology. The haemodynamic consequences of lead to syncope by various mechanisms (box ventricular tachycardia depend on the rate of 2). Young age and ventricular arrhythmias are highly predictive of syncope in patients with the tachycardia and on cardiovascular auto- 22 nomic tone.18 Syncope or presyncope caused hypertrophic cardiomyopathy. Extreme out- by supraventricular tachycardia is believed to flow tract obstruction secondary to catecho- be associated with altered vasomotor tone lamine stimulation and an association with the 19 WPW syndrome are additional mechanisms for

independent of the tachycardia rate. Atrial on September 29, 2021 by guest. Protected copyright. fibrillation associated with the WolV- syncope in hypertrophic cardiomyopathy. Parkinson-White (WPW) syndrome can lead Recurrent pulmonary emboli can give rise to to extremely rapid ventricular rates, causing syncope in the absence of other symptoms. syncope. Polymorphic ventricular tachycardia Syncope occurs in over 10% of patients with related to a long QT interval is a well pulmonary embolism and is more likely to recognised cause of syncope and sudden death. occur with large emboli. Massive pulmonary In the older patient, bradyarrhythmias embolism can obstruct the flow of blood in the caused by sinus node dysfunction or conduc- pulmonary artery leading to reduced cardiac tion system disease are important causes of output.23 Smaller pulmonary emboli can give syncope. Sick sinus syndrome denotes a rise to vagally mediated bradyarrhythmias; complicated rhythm disturbance involving im- these occur because of activation of pulmonary paired sinoatrial impulse formation or conduc- or ventricular stretch receptors, in an analo- tion. In patients with sick sinus syndrome, gous fashion to neurocardiogenic syncope.24 around 50% or more have the bradycardia- Myocardial infarction is most likely to tachycardia syndrome, usually manifesting as present atypically as syncope in the elderly; sinus bradycardia alternating with paroxysmal probably because of transient bradyarrhyth- atrial tachycardia, atrial fibrillation, or atrial mias resulting from a reflex bradycardia (the flutter. Patients with a sick sinus node or Bezold-Jarisch reflex); otherwise it is a rare bradycardia-tachycardia syndrome may experi- direct cause of syncope.6 Other mechanical ence syncope from sinus arrest or following cardiovascular causes of syncope are relatively spontaneous conversion from a supraventricu- rare, such as left atrial myxoma, severe mitral lar tachycardia to sinus rhythm with a long stenosis, or prosthetic valve dysfunction.

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with no measurable change in blood pressure, Summary points heart rate, EEG pattern, or transcranial blood x The commonest form of syncope, the flow.9 This finding has been termed “psycho- “vasovagal” faint, is associated with a genic syncope” and is believed to be a somato- good prognosis. form disorder. x Elderly people are susceptible to acute changes in cerebral blood flow, 1 Kapoor WN. Evaluation and management of the patient with syncope. JAMA 1992;268:2553–60. predisposing them to syncope. 2 Kapoor WN. Evaluation and outcome of patients with syn- Syncope in the presence of structural cope. Medicine 1990;69:160–75. x 3 Manolis AS, Linzer M, Salem D, et al. Syncope: current heart disease and a low left ventricular diagnostic evaluation and management. Ann Intern Med 1990;112:850–63. ejection fraction is associated with a high 4 Lipsitz LA, Wei JY, Rowe JW.Syncope in the elderly, institu- mortality rate. tionalised population: prevalence, incidence, and associated risk. QJMed1985;55:45–55. 5 Gowers WR. A lecture on vagal and vasovagal attacks. Lan- cet 1907;173:1551–3. Neurological and psychiatric diseases 6 Wayne HH. Syncope: physiological considerations and an analysis of the clinical characteristics in 510 patients. Am J In the absence of accompanying focal neuro- Med 1961;30:418–38. logical symptoms and signs, syncope from cer- 7 Benditt DG. Neurally mediated syncopal syndromes: pathophysiological concepts and clinical evaluation. PACE ebrovascular disease is rare. Transient ischae- 1997;20:573. mic attacks caused by vertebrobasilar 8 Shalev Y, Gal R, Tchou PJ, et al. Echocardiographic demonstration of decreased left ventricular dimensions and insuYciency may cause syncope. Those af- vigorous myocardial contraction during syncope induced by fected tend to be elderly men with ischaemic head-up tilt. J Am Coll Cardiol 1991;18:746–51. 9 Grubb BP, Kosinski D. Tilt table testing: concepts and limi- heart disease. Concurrent neurological symp- tations. PACE 1997;20:781–7. toms include mainly vertigo, ataxia, or sensory 10 Abboud FM. Neurocardiogenic syncope. N Engl J Med 25 1993;328:1117–1120. disturbances. Transcranial Doppler ultra- 11 Sutton R, Peterson M, Raviele A, et al. Proposed sonography has been used during head up tilt classification for tilt-induced vasovagal syncope. Eur J Cardiac Pacing Electrophysiol 1992;2:180–3. testing to demonstrate cerebral vasoconstric- 12 Abi-Samra F, Maloney JD, Fouad-Tarazi FM, et al. The tion associated with syncope that precedes, or usefulness of head up tilt testing and hemodynamic investi- gations in the work up of syncope of unknown origin. PACE even occurs in the absence of, systemic 1988;11:1202–14. hypotension.926 This phenomenon has been 13 Thomas JE. Hyperactive carotid sinus reflex in carotid sinus syncope. Mayo Clin Proc 1969;44:127–39. termed cerebral syncope. 14 Wagshal AB, Huang SKS. Carotid sinus hypersensitivity. In: Distinguishing seizures from syncope can be Grubb BP, Olshansky B, eds. Syncope: mechanisms and management. Armonk, NY: Futura, 1998:281–95. diYcult, especially if a patient experiences 15 Gaggioli G, Brignole M, Menozzi C, et al. Reappraisal of the “convulsive syncope.” Convulsive movements, vasodepressor reflex in carotid sinus syndrome. Am J Cardiol 1995;75:518–21. similar to tonic-clonic seizure activity, can 16 Mathias CJ. The classification and nomenclature of occasionally result from cerebral hypoxia sec- autonomic disorders: ending chaos, resolving conflict and hopefully achieving clarity. Clin Auton Res 1995;5:307–10. ondary to cerebral hypoperfusion. While neu- 17 MiddlekauV HR, Stevenson WG, Saxon LA. Prognosis after rally mediated syncope may mimic seizure-like syncope: impact of left ventricular function. Am Heart J 1993;125:121–7. activity, it should also be acknowledged that 18 Huikuri HV, Zaman L, Castellanos A. Changes in seizure foci in certain cerebral sites (particu- spontaneous sinus node rate as an estimate of cardiac autonomic tone during stable and unstable ventricular tachycar- http://pmj.bmj.com/ larly the temporal lobe) may be the source of dia. J Am Coll Cardiol 1989;13:646–52. apparent neurally mediated syncopal events. 19 Leitch JW, Klein GJ, Yee R, et al. Syncope associated with supraventricular tachycardia: an expression of tachycardia Localised seizure activity may initiate the reflex rate or vasomotor response? Circulation 1992;85:1064–71. arc previously described, leading to hypoten- 20 Moss AJ, Davis RJ. Brady-tachy syndrome. Prog Cardiovasc Dis 1974;16:439–545. sion and bradycardia. 21 Jackman WM, Friday KJ, Anderson JL, et al. Idiopathic long The prevalence of psychiatric illness in QT syndrome: a critical review, new clinical observations and a unifying hypothesis. Prog Cardiovasc Dis 1988;31:115– patients with syncope of unknown origin is 72. around 24%.27 Hyperventilation, particularly 22 Nienaber CA, Hiller S, Spielman RP, et al. Syncope in hypertrophic cardiomyopathy: multivariate analysis of prog- on September 29, 2021 by guest. Protected copyright. in panic disorder, leads to hypocapnia, causing nostic determinants. J Am Coll Cardiol 1990;15:948–55. a transient increase in cerebrovascular resist- 23 Thames MD, Alpert JS, Dalen JE. Syncope in patients with pulmonary embolism. JAMA 1977;238:2509–11. ance coupled with simultaneous peripheral 24 Simpson RJ, Podolak R, Mangano CA, et al. Vagal syncope vasodilatation. Vasovagal syncope can be during recurrent pulmonary embolism. JAMA 1983;249: 390–3. caused by acute stress or fear and is therefore 25 Davidson E, Rotenbeg Z, Fuchs J, et al. Transient ischemic implicated in anxiety, panic, and major depres- attack-related syncope. Clin Cardiol 1991;14:141–4. 26 Grubb BP, Samoil D, Kosinski D, et al. Cerebral syncope: sive disorders. Certain individuals continue to loss of consciousness associated with cerebral vasoconstric- have recurrent unexplained syncope despite tion in the absence of systemic hypotension. Pacing Clin thorough investigation. Some patients may Electrophysiol 1998;21:652–8. 27 Jeong H, Kapoor W. Psychiatric illness and syncope. Cardiol actually experience syncope during tilt testing, Clin 1997;15:269–75.