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History of Syncope in the Cardiac Literature

David S. Cannom⁎

UCLA School of Medicine, Los Angeles, CAGood Samaritan Hospital, Los Angeles, CA

A R T I C L E I N F O

Statement of Conflict of Interest: see page⁎ Address reprint requests to David S. CannomE-mail address: dcannom@lacard.com.

0033-0620/$ – see front matter © 2013 Publishttp://dx.doi.org/10.1016/j.pcad.2012.11.013

A B S T R A C T

Keywords:

The rich cardiology literature of the past 100 years in which the most important forms ofsyncope are described – including vasodepressor syncope, postural orthostatichypotension, and Morgagni-Stokes-Adams syncope – is fascinating. These conditionswere of interest to some of our most astute clinicians who were also excellent writers. Wethus have available for review the remarkable description of patients with these entitieswritten by clinicians such as Soma Weiss, Sir Thomas Lewis, Laurence Ellis, David Sherf,Milton Shy, and Glenn Drager. In their detailed clinical descriptions we identify thepertinent symptoms and signs we see in our patients today years later. A group ofbrilliant basic physiologists and cardiologists was able to explain the altered physiologyresponsible for the clinical presentations of syncope patients. Basic investigations weredone by investigators such as Arnold Weissler, James Warren, J. Erlanger and clinicalcardiologists including John Parkinson, Cornelio Papp, and William Evans to name just afew. Between the early precise clinical descriptions and the subsequent thoroughdefinition of the altered physiology, a surprisingly complete understanding of theseclinical entities was established 50 years ago. It took another generation before cliniciansdeveloped methods of caring for patients with these clinical entities. The development ofimplantable devices, e.g., pacemakers and defibrillators, for use in Morgagni-Adams-Stokes attacks is the best example of curative therapies catching up with clinicaldiagnoses. Other more simple relevant therapies were developed for patients withvasodepressor syncope and postural orthostatic hypotension. Finally, the developmentand acceptance of clinical guidelines for the treatment of these conditions brought theoriginal clinical observations and description of altered physiology into focus and usheredin a new generation of improved care for these patients.

© 2013 Published by Elsevier Inc.

SyncopeHistoryPhysiology

Brief overview of early citations of syncope

The initial contribution to this special edition focuses on thehistory of our understanding of syncope and on how theevolution of these insights enlightens our approach tothe syncope patient today. There are many interesting parts

338., 1245 Wilshire Boulevar

hed by Elsevier Inc.

to this story. Our understanding of the responsible patho-physiologic mechanisms of syncope occurred only in the last70 to 100 years. Some of themost astute clinicians inmedicinewrote the first clinical descriptions of syncope. In the 1930sand later the first descriptions of the pathophysiology ofsyncope were presented by basic scientists who studied

d, #703 Los Angeles, CA 90017.

Abbreviations and Acronyms

BPM = beats per minute

HSAN = hereditary sensory andautonomic neuropathies

OH = orthostatic hypotension

PAF = primary autonomic failure

POTS = postural orthostatictachycardia syndrome

RF = radiofrequency

VDS = vasodepressor syncope

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altered cardiac hemo-dynamics by both non-invasive and invasivetechniques. The goalof these studies wasto describe the alteredpathophysiology thatoccurred during synco-pe; this was done bril-liantly and ultimatelyled to the more recent-ly described treatmentparadigms.

There are at least

three different clinical conditions that are characterized as‘syncope’ —and there are important differences in theirpathophysiology. Each will be discussed separately. The goalof this discussion is to highlight the key historical descriptionsand the discovery of important basic mechanisms that adviseour treatment of these conditions today. For purposes of thissection we will consider: vasodepressor syncope (VDS),orthostatic hypotension, and Stokes-Adams attacks.

Vasodepressor syncope

The review of Vasodepressor Syncope by Weissler andWarren carefully describes the early history of the recognitionof this phenomenon.1 This account is broadened in theirchapter on syncope in Hurst's ‘The Heart: Arteries and Veins’textbook of cardiology.2 Both of these physicians worked atDuke and were gifted basic physiologists. They were joined byEugene Stead and Henry McIntosh in many of the pivotalpapers describing this type of syncope.

The early descriptions of the role of upright posture incausing loss of consciousness date back to 1740 whenHoffman described otherwise healthy patients who devel-oped severe degrees of collapse upon standing.3 Subse-quently, in 1861 Augustus Waller, then working in England,reported that digital pressure behind the angle of the jaw, amethod considered to be useful for defining the functions ofthe vagus nerve, causes a syndrome of hyperventilation,epigastric discomfort, and tachycardia followed by bradycar-dia and finally by loss of consciousness.4 This earlydescription suggested the role of the vagus in causation ofVDS. In 1891 Foster thought that this form of syncope wasdue to vagal inhibition of the heart and stated “that allcases of simple fainting from emotion, pain, digestivetroubles, etc. (as distinguished from syncope due to actualheart disease) are instances of vagus inhibition of theheart.5” This term is somewhat unclear as the “inhibitionof cardiac function” is due to vagal overactivity not vagalnerve inhibition itself. But the case for an autonomic causeof VDS was made.

There was ongoing debate in the 1930s as to whetheratropine could block the vagal effects that caused VDS. In 1931Lewis, who is also generally credited with coining the term‘vasovagal syncope,’ concluded that atropine may abolish thebradycardia associated with VDS but did not affect the clinical

picture of syncope.6 Further work using more moderntechniques amplified the understanding that cardiac contrac-tile dysfunction was not the cause of syncope. Weiss andcoworkers used orally administered nitrates and noninvasiveplethysmographic measure of upper extremity blood flow inthe warmed (45 °C) forearm and found no change in cardiacoutput during circulatory collapse.7 Finally, peripheral dyeinjection techniques gave conclusive proof that cardiacoutput either remains the same or falls only slightly duringthe initial phase of VDS.

Some astute clinicians of the day took great care in theirobservations of such patients and provided eloquent descrip-tions of vasodepressor syncope episodes. In 1931 Weiss wrote:

In the severe type with rapid onset the patient collapsesinstantly without warning. The body lies crumpled andmotionless. The face and the body surface are ghastlypale. The pupils are usually dilated, and the conjunctivareflexes are absent. Respiration is usually either shallowand slow, or deep and sighing. The heart sounds are slowor normal in rate and barely audible…There may berather slow chronic movements localized over the facialmuscles or over the upper part of the body: in rareinstances they may be generalized. There is no othercondition including the deepest coma which so closelyresembles death. No wonder that a simple benignsyncope is often described as ‘an attack in which thepatient almost died.8

A similar and equally moving description was publishedby Sir Thomas Lewis in the British Medical Journal.6 Lewisexpands the account by noting that such fainting attacksoccurred in young soldiers in ill health, were common afterillness or chronic infection and occurred in overcrowdedrooms.6 BothWeiss and Lewis noted that in some patients theonset of the episode was sudden and that VDS can occur inthe sitting position. Lewis was clear that the slow pulse is dueto vagal slowing which responds to atropine but that themaincause of the fall of blood pressure and the enfeeblement of thepulse in these attacks is independent of the vagus and lies inthe blood vessels. He stated that the cause of such syncopalspells is mainly vasomotor and not vagal. This observation isthe genesis of the term ‘vasovagal’ (most often attributedto Lewis but which in fact he borrowed from an earlier timenineteenth century in which it had been used for anapparently different problem) or vasodepressor syncopewhich acknowledges the role of the vagus nerve in causingthe bradycardia and vasomotor collapse as the cause of thefall in blood pressure.

Recent studies have shown that during a VDS spell amarked fall in peripheral vascular resistance due to suddendilatation of vascular beds especially in the voluntarymusclesand large venous beds (e.g., splanchnic vessels) is an essentialelement in the decreased arterial blood pressure. This occurswith inadequate and at times without any compensatoryreaction of the heart; this vascular effect may be partially dueto vagal activity but this same response occurs even ifthe vagus nerve is blocked.9 Perhaps marked centralhypovolemia due to substantial venous pooling makes itimpossible for the heart to compensate sufficiently for adeclining blood pressure.

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George Engel, a psychiatrist at the University ofRochester, thought that VDS was a partial inhibition ofthe “fight or flight” mechanism described by WalterCannon10 in his studies of the physiologic changes duringfear, pain and anger. Engel noted that physiologic changesdescribed by Cannon (including an increased heart beat,increased blood flow to muscle, decreased blood flow toskin and the gastrointestinal tract, augmented ventilation,and sweating) at times may not be employed by theanimal in situations of great stress. Instead, these physi-ologic features may be inhibited leading to a slow pulse,muscle flaccidity and finally syncope.11 Engel states thatVDS seems to occur in settings of real or threateneddanger and that appropriate action by the animal or apatient is inhibited or impossible. Charles Darwin madesimilar observations in animals, especially birds, whichfaint.12 Some suggest that the faint, like playing dead, maydiscourage a predator attack and thereby ironically beprotective.

It is clear that these astute observations of the pastcentury, none occurring more recently than 50 years ago,identified the clinical picture and pathophysiology ofvasodepressor syncope. Only in the past 20 years or so havetherapies begun to catch up with the known underlyingmechanisms causing the problems.

Other forms of syncope including post micturation synco-pe, reflex asystole and carotid sinus syncope are extensions ofVDS pathophysiology.

Postural orthostatic hypotension: primaryautonomic failure

The first of the autonomic failure syndromes was describedby Bradbury and Eggleston in 1925.13 They presented threecases of what they called “idiopathic orthostatic hypotension”because of its contrast with VDS. The characteristics of thissyndrome in the original description included a syncopalattack when the patient stood and was associated with amarked drop in blood pressure, a slow and unchanging pulse,anhidrosis, increased distress during the summer, a slightlylow basal metabolic rate, and indefinite and slight changes inthe central nervous system.13 Subsequent definitions haveexpanded the clinical profile to include disturbed bowel,bladder, sudomotor, thermoregulatory and sexual function.14

This expanded syndrome is now referred to as primaryautonomic failure (PAF).

The PAF syndrome is due to an overall deficiency inautonomic function and signifies failure of reflex hemody-namic adaptation to upright posture. There is a symptomaticdifference between VDS and primary autonomic failure.During the presyncopal period in PAF patients there is littleor no change in pulse rate, and those affected do not typicallyexhibit pallor, sweating and epigastric distress as is seen inVDS.2

Progress in the definition of orthostatic hypotensionsyndromes has been due to the careful reporting of clinicalcases dating back to Eggleston. An additional six cases were

described by Ellis and Haynes and in four cases they describedassociated neurologic disease (including patients with tabes,syringomyelia and hematomyelia).15

Circulatory dynamics in PAF patients were measured, andin the erect position cardiac output was normal.15 Ephedrinewas the only drug useful in treatment. Ellis and Haynes15

reasoned on clinical grounds that “postural hypotensionresults from a failure of the normal sympathetic vasomotorreflex to produce vasoconstriction when the subject assumesan erect position.” They similarly found no hemodynamicabnormalities to explain postural hypotension and absentreflex vasoconstriction when standing. To explain the diffuseend organ sympathetic nervous system failure they reasonedthat the area of the brain controlling the failed reflex lies in asympathetic center or an afferent pathway. Subsequentstudies have not clarified the defect in the sympatheticnervous system. Parkinsonism, diabetes, and alcohol abusecan also cause PAF.

An even more serious form of orthostatic hypotension dueto autonomic failure was described by Shy and Drager in1960.16 In addition to severe orthostatic hypotension thesepatients have iris atrophy, urinary and rectal incontinence,loss of sweating, external ocular palsy, rigidity, and impo-tence.14 This deadly syndrome has been called multiplesystem atrophy and is associated with amyloidosis (primaryor hereditary), HSAN (hereditary sensory and autonomicneuropathies) type III (also called familial dysautonomia),idiopathic immune-mediated autonomic neuropathy, Sjogren'sSyndrome and paraneoplastic autonomic neuropathy.17

The papers which describe the condition we now callprimary autonomic deficiency, such as that by Ellis andHaynes, consist of carefully presented clinical profiles butinclude no associated experimental or hemodynamic databesides simple blood pressure determinations. These papersdo not include elegant experimental data as noted in thevasodepressor literature (previously cited) which describesbasic mechanisms responsible for syncope in these patients.

It is important to separate the simpler and more stableforms of PAF from the more lethal forms to help with bothtreatment and clinical prognosis. The complicated andintense clinical care of such patients is often best done intertiary centers with sufficient infrastructure for prolongedclinical care and frequent adjustment of medications.

A recent new subgroup of autonomic insufficiency, calledpostural tachycardia syndrome or POTS, is characterizedby an excessive increase in heart rate when assumingthe upright posture.18–21 These patients, typically youngwomen, develop pulse rates of 150 BPM or more when uprightbut they do not become hypotensive. The initial recognitionwas reported by Shandorf and Low19 but perhaps these aresimilar to the neurasthenic patients described by Lewis,although the latter were mainly young men. In fact, in arecent review, Low et al. postulated that POTS over the yearshas been what clinicians previously called neurocirulatoryasthenia and soldier's heart syndrome.22 There is consider-able overlap of the POTS patient with those diagnosed ashaving chronic fatigue syndrome; many of the latter groupshave positive tilt tests and some respond to typicaldysautonomia therapy.23

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POTS patients are highly symptomatic and experiencefatigue, palpitations, near syncope, lightheadedness, dizzi-ness and early morning “brain fog.” This condition isimportant to recognize as the rapid pulse may suggestinappropriate sinus tachycardia may lead to inappropriatetherapies such as attempts at radiofrequency (RF) ablation ofthe sinus node.

The exact cause of the underlying autonomic dysfunctionis unknown but altered peripheral vascular function likelyplays a role. Often the condition is misdiagnosed as apsychological disturbance and patients can be mistreated bysomeone without an interest in POTS.

Morgagni-Adams-Stokes attacks

Stokes-Adams disease describes a major mechanism ofsyncope which is of cardiac origin and is due to alterationsin cardiac rhythm; these rhythm changes may be associatedwith either a rapid or slow heart rate which can be eitherregular or irregular. The clinical entity itself was first reportedin the eighteenth century by a variety of observers, the first ofwhom was Huchard who proposed the phrase Stokes-Adamsdisease.24 All of the initial reports are in English.25,26

Morgagni in 1761 described epileptiform attacks characterizedby a slow pulse.25

Early observers detailed the clinical features and correlat-ed syncopal events with an unusual pulse. The pulse may beslow between attacks but is slower or absent during attacks.Early observers correlated the relationship between the pulseand clinical attacks.27 The study of the AV conduction systemin the late 19th century by Kent in England and His inGermany led to an understanding of atrioventricular block asa possible cause of syncope and ultimately resulted inpublication of a case report in 1905 that identified heartblock using a sphygmograph.26 The details of these investi-gations are worth reading for their intuitive genius.27

The advent of ECG recordings in manuscripts written bythe first generation of cardiologists (including White andLevine) quickly drew attention to the relationship of AV blockand syncope. Parkinson, Papp and Evans in the 1940s addedother ECG conditions that cause syncope including cardiacstandstill, ventricular tachycardia and ventricular fibrillation.The Stokes-Adams syndrome and its poor prognosis wererecognized early.

Scherf and Bornemann called the syndrome “a rehearsalfor death.28” They describe a typical patient who has“darkness in front of his eyes, dizziness or lightheadedness.In an episode that interrupts the circulation for only3–4 seconds the patient behaves as in a petit mal attack.Immediately thereafter he continues his conversation orother activities oblivious that something has happened.” Ifthe standstill of circulation is 10 seconds then a “strikingpallor appears followed by muscular twitching, cyanosis andmaximally dilated pupils.” In an episode lasting 20 to45 seconds tonic-clonic convulsions and release of sphinc-ters occurs. Attacks lasting longer than 2 ½ minutes arerarely survived. The key element in such patients was thatcollapse is immediate and often injury to the patient results.

When cardiac contractions resume the patient's face willflush and full consciousness returns.

Early investigators recognized the seriousness of theattacks and were able to correlate symptoms with the newtechnology of the ECG. The rhythms initially describedincluded paroxysmal supraventricular tachycardia or ven-tricular tachycardia, ventricular fibrillation, episodes of AVblock, and sino-atrial block. Differential diagnosis includedepilepsy, vasovagal syncope, orthostatic hypotension andintrinsic cardiac disease including aortic stenosis andcoronary disease.28

Over the past 20 years cardiac electrophysiologists with aspecial interest in genetics have described disease states thatoccur primarily in the young, are inherited on an autosomaldominant basis, and are an important cause of syncope andeven sudden death in these patients with the geneticabnormality. The syndromes with most definitive patternsof inheritance include the long QT syndrome and Brugadasyndrome. These clinical entities as well as those with lesswell defined patterns of inheritance such as hypertrophiccardiomyopathy, arrhythmogenic right ventricular dysplasia,and familial dilated cardiomyopathies are now intensivelystudied to enable better risk stratification and more selectivetreatment. These syndromes are the newest and best studiedentities that are part of the family of clinical entities causingMorgagni-Adams-Stokes attacks.

Fortunately, the cardiac pacemaker described by Zoll in195229 and later the implantable cardioverter defibrillatorconceived by Mirowski and Mower in 197130 became availableand changed the prognosis of this clinical entity dramaticallyin some cases.

Conclusion

Early reports describing the various forms of syncope arenotable for their careful and even laborious observations byastute clinicians based entirely on careful observations in afew patients. These initial observations led to a basicunderstanding of causal mechanisms such as hypotensionin vasodepressor syncope and heart block in Stokes-Adamsdisease; more recent reports examining these conditions onlyconfirm the initial clinical descriptions.

The history of cardiology is a history of bedside medicineand is an art in danger of being lost. We are nowencountering a generation of clinicians who may performtests before they have assessed the patient's history andphysical findings. The tendency is accentuated by financialpressures, liability issues, and requirements imposed bypayors and coders, as well as the demands of the electronicmedical record and the use of non-physicians in informationgathering. These tendencies do not serve the patient well,and in the care of the patient with transient loss ofconsciousness and presumed syncope can be dangerous. Athorough history by a capable physician is often all that isnecessary to make a diagnosis and begin therapy. The majorexception is the patient with cardiac syncope due to anintermittent but difficult to document arrhythmia wherecareful testing is necessary.

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Statement of Conflict of Interest

All authors declare that there are no conflicts of interest.

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