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48
SYNCOPE
patients who have atrioventricular or sinoatrial block lasting greater than 10seconds follow‑
ing a 20mg IV bolus of ATP. In a single‑blind multicenter study in 80 elderly patients (mean age
75.9
± 7.7 years) with syncope of unknown origin and positive ATP test, active pacing reduced
recurrent syncope from 66% to 21% (hazard ratio, 0.25; 95% condence interval, 0.12–0.56) when
compared to back‑up pacing.
39
Although this trial supports the use of an ATP test in this group of
patients, guidelines have not endorsed it on a broad basis.
Exercise Stress Testing
Exercise stress testing (EST) is often used in the investigation of the patient with syncope, particu‑
larly if syncope has occurred during or shortly after exertion. Heart rate, blood pressure, and ECG
analysis (heart rhythm, conduction, ST‑T waves, and QT dynamics) during and immediately after
exercise may uncover syncope attributed to coronary ischemia, tachyarrhythmias (catecholaminer‑
gic polymorphic ventricular tachycardia or ventricular brillation/tachycardia), exercise‑induced
AV block, or reex vasodilation.
Patients with suspected ischemia should have further evaluation.
Evaluating the end of recovery (4minutes after cessation of exercise) corrected QT interval (QTc)
can help to differentiate LQTS from unaffected individuals. At this time point, a QTc cutoff value
of 445ms has a sensitivity and specicity of 92% and 88%, respectively, for distinguishing patients
with LQTS from those who do not.
40
This simple cutoff and exercise testing is more accurate in
females, though it performs well in both sexes.
41
Bidirectional VT or polymorphic VT is induced
during exercise in 63% of patients with CPVT.
36
Structural Heart Disease Evaluation
As the presence of structural heart disease carries a poor prognosis in the patient who has had
syncope, it is essential to consider this in the initial evaluation. In patients suspected of hav‑
ing structural heart disease including those with symptoms, risk factors, physical ndings, or
a family history of structural heart disease or those with an abnormal ECG, cardiac imaging is
recommended.
3
The current imaging test of choice in the evaluation of structural heart disease
is echocardiography as it is non‑invasive, carries no radiation exposure, and is highly accessible.
Further evaluation with cardiac MRI can be considered when abnormalities are suspected but not
denitive following echocardiography, or when occult cardiomyopathy is suspected.
Conclusion
A comprehensive understanding of the diagnostic tools for the investigation of syncope and how
to use them is critical in the evaluation of a patient who has had syncope. By combining the infor‑
mation gained from the initial evaluation of history, physical examination, and ECG, the clinician
can direct further testing to further risk stratify and diagnose the syncope etiology, thereby reduc‑
ing anxiety and syncope‑associated morbidity and mortality. Extended monitoring in multiple
formats is increasingly accessible to detect or exclude a culprit arrhythmia.
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22. Krahn AD, Klein GJ, Yee R, Takle‑Newhouse T, Norris C. Use of an extended monitor‑
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cope with a new subcutaneously implantable loop recorder. Reveal‑Investigators. Europace.
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tional diagnostic testing versus a prolonged monitoring strategy. Circulation. 2001;104:46–51.
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in patients with syncope: randomized assessment of syncope trial. J Am Coll Cardiol.
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26. Connolly SJ, Sheldon R, Thorpe KE, et al. Pacemaker therapy for prevention of syncope in
patients with recurrent severe vasovagal syncope: Second Vasovagal Pacemaker Study (VPS
II): a randomized trial. JAMA. 2003;289:2224–2229.
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Etiology Investigators. Pacemaker therapy in patients with neurally mediated syncope and
documented asystole: Third International Study on Syncope of Uncertain Etiology (ISSUE‑3):
a randomized trial. Circulation. 2012;125:2566–2571.
28. Miyamoto K, Yokokawa M, Tanaka K, et al. Diagnostic and prognostic value of a type 1
Brugada electrocardiogram at higher (third or second) V1 to V2 recording in men with
Brugada syndrome. Am J Cardiol. 2007;99:53–57.
29. Obeyesekere MN, Klein GJ, Modi S, et al. How to perform and interpret provocative testing
for the diagnosis of Brugada syndrome, long‑QT syndrome, and catecholaminergic polymor‑
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30. Ackerman MJ, Khositseth A, Tester DJ, Hejlik JB, Shen WK, Porter CB. Epinephrine‑induced
QT interval prolongation: a gene‑specic paradoxical response in
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32. Shimizu W, Noda T, Takaki H, et al. Epinephrine unmasks latent mutation carriers with
LQT1 form of congenital long‑QT syndrome. J Am Coll Cardiol. 2003;41:633–642.
33. Krahn AD, Gollob M, Yee R, et al. Diagnosis of unexplained cardiac arrest: role of adrenaline
and procainamide infusion. Circulation. 2005;112:2228–2234.
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probe phenotype/genotype discordance in congenital long QT syndrome. Am J Cardiol.
2005;96:1425–1430.
35. Viskin S, Rosso R, Rogowski O, et al. Provocation of sudden heart rate oscillation with
adenosine exposes abnormal QT responses in patients with long QT syndrome: a bedside
test for diagnosing long QT syndrome. Eur Heart J. 2006;27:469–475.
36. Sy RW, Gollob MH, Klein GJ, et al. Arrhythmia characterization and long‑term outcomes in
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38. Meregalli PG, Ruijter JM, Hofman N, Bezzina CR, Wilde AA, Tan HL. Diagnostic value
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Electrophysiol. 2006;17:857–864.
39. Donateo P, Brignole M, Menozzi C, et al. Mechanism of syncope in patients with positive
adenosine triphosphate tests. J Am Coll Cardiol. 2003;41:93–98.
40. Chattha IS, Sy RW, Yee R, et al. Utility of the recovery electrocardiogram after exercise:
a novel indicator for the diagnosis and genotyping of long QT syndrome? Heart Rhythm.
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41. Yee LA, Han HC, Davies B, et al. Sex differences and utility of treadmill testing in long‑QT
syndrome. J Am Heart Assoc.2022;11:e025108.
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SYNCOPE
52 DOI: 10.1201/9781003415855 -7
6 Reex Syncope
6A
Reex Syncope
Vasovagal Syncope
William H. Parker, Mark W. Chapleau, and Brian Olshansky
INTRODUCTION
Vasovagal syncope (VVS), also known as neurally mediated syncope or the common faint, results
from paradoxical reex disruption of effective cardiovascular regulation, resulting in transient
failure to maintain homeostasis and proper blood ow to vital organs, particularly the brain.
Reex syncope, due to a specic trigger, is termed situational syncope,
1
but the overarching mech‑
anism is related to the same vasovagal reex. Here, we discuss the causes for and mechanisms of
reex VVS, dene specic situational triggers, and consider diagnostic and therapeutic approaches
to these common problems.
OVERVIEW OF VVS
Observations regarding fainting date back hundreds of years, but Sir Thomas Lewis, in 1932,
characterized vasovagal syncope as a combination of vagal and vasomotor effects.
2
The incidence
of clinically apparent reex syncope in the general population is characterized by a bimodal distri‑
bution with peak incidences in teenagers and the elderly.
1
However, no evidence indicates that the
vasovagal response itself is necessarily pathologic. The lifetime incidence in females can approach
50% compared to 25% in males,
3
but for most, VVS is a singular event triggered by some specic
stimulus. Others have recurrent unexplained episodes that are debilitating.
A careful history is the essential rst step to securing a diagnosis of reex syncope, but further
diagnostic evaluation, including electrocardiographic (ECG) monitoring
4
and tilt testing, may
be required
5
even though the tilt test has problems with sensitivity and specicity
6
as it does not
emulate what happens in real life. Monitoring alone does not explain the mechanism of asystolic
fainting nor does it correlate the exact temporal relationship of asystole to syncope. Episodes often
begin with a prodrome that can include nausea, diaphoresis, pallor, or a diminution in vision or
hearing before collapse. During recovery, profound fatigue is common. A point‑scoring question‑
naire
7
has an 89% sensitivity and 91% specicity to diagnose VVS even though the gold standard
comparison to diagnose VVS is in question.
A reproducible trigger may be present (often in older patients). Underlying acute and transient
pathology may be responsible: acute myocardial infarction, aortic stenosis, hypertrophic obstructive
cardiomyopathy, pulmonary hypertension, pulmonary embolus, pericardial effusion, and cardiac
tamponade are potential causes. In others, daily activities (deglutition, cough, defecation, micturi‑
tion, vomiting, prolonged standing, heat, noxious stimuli, and pain) can be the precipitant. For the
latter group, episodes can be reproducible under similar circumstances or exist as singular events.
Although often considered pathologic, VVS can be a physiologic defense mechanism to protect the
brain from ischemic injury. It is not necessarily an abnormal reex. Much like a turtle’s autonomic
adjustment to maintain necessary cerebral oxygenation when diving underwater for prolonged peri‑
ods
8
or a bear’s vagal activation to reduce energy consumption when hibernating,
9
so too does our
autonomic nervous system attempt to strike a perfect balance to meet instantaneous cardiovascular
needs. Loss of consciousness with concomitant loss of muscle tone caused by VVS in humans may
have specic benets as part of the ght/ight response and may be life‑saving during drowning.
8
Cerebral perfusion requires 15%–20% of the cardiac output. Disruption of adequate cerebral
blood ow for as little as 6seconds, particularly to the claustrum, the paraventricular nucleus,
10
and the reticular activating system in the brainstem, can cause syncope. While VVS is generally an
isolated low‑risk event aside from the risk of injury due to falling, recurrent forms of VVS, whether
it be idiopathic in younger individuals or related to the cardiovascular, neurological, or metabolic
condition, require further investigation and, possibly, treatment.
11
CLINICAL FEATURES OF VVS
When VVS affects young individuals in good health, a precursor marked by nausea, pallor, and
excess diaphoresis aligned with heightened vagal activity is common.
12
Other prodromal symp‑
toms include lightheadedness, change in perception of temperature, diaphoresis, palpitations,
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6A VASOVAGAL SYNCOPE
53
gastrointestinal upset, visual changes, auditory manifestations, and sensory alterations. Usual
triggers and preliminary symptoms provide strong indicators of an overt impending vasovagal
response, but a prodrome may or may not be present or associated with a faint. Consequently, VVS
may be hard to diagnose. Thus, 20%–30% of those who pass out from an undened cause most
likely have VVS. In the elderly, the history might not conform to the classical pattern observed in
younger patients; there may be a specic trigger.
13
VVS typically occurs while sitting upright or standing, especially for long periods of time. In
addition to prolonged standing, VVS triggers include emotional stress, pain, or medical proce‑
dures.
4
In younger individuals, this may not be triggered by a dening event. Situational syncope
in older adults may have unique triggers including deglutition, cough, etc. VVS is usually brief
(seconds to minutes), yet fatigue, after recovery, might persist. Alternatively, arrhythmia‑mediated
syncope tends to be abrupt, lacking autonomic warning signs or post‑event weariness. Seizure
disorder may have a prodrome but also has a prolonged recovery.
Current European Society of Cardiology (ESC) guidelines reference a “low BP phenotype”
as a subpopulation of reex syncope.
4,14
This is better elucidated in a subsequent multicohort
cross‑sectional study demonstrating a different resting hemodynamic prole among patients with
reex syncope versus the general population. Namely, patients with reex syncope have, on aver‑
age, lower systolic blood pressure (BP), higher diastolic BP, lower pulse pressure, and higher heart
rate (HR). These data suggest reex syncope patients have lower stroke volume and lower venous
return and rely on chronic activation of compensatory mechanisms to maintain cardiac output.
14,15
Recurrence of reex syncope varies based on individuals and triggers, but recurrence is com‑
mon and yet often difcult to predict. In the ISSUE‑3 trial, that compared the recurrence of syn‑
cope in pacemaker groups to control groups, 57% of the control group experienced a recurrence of
syncope over two years.
16
Other data conrm a similar likelihood of recurrence. In patients with
recurrent VVS, episodes can occur in clusters or storms of multiple syncopal events over days to
weeks, followed by prolonged syncope‑free periods.
17
The likely inciting initiating trigger may be
excess sympathetic activation. The resulting vasovagal reex can be a transient and self‑limited
phenomenon but may present in a malignant and recurrent fashion
17
which can even present as a
“storm”. Mechanisms driving clusters and periods of remission are uncertain.
Recurrent VVS appears to be more prevalent in certain families, with a higher likelihood of both
biological parents experiencing fainting, suggesting a potential genetic component to the disease.
18
One analysis of pooled family data reported that 36%–51% of VVS patients had a family member
who fainted versus 28% of controls.
19
Various studies point to genomic sites linked to VVS, but
specic genes and pathways remain largely unknown. However, one multigenerational kindred
candidate gene study identied three genes associated with VVS.
20
This represents an area of
ongoing study.
21
AUTONOMIC (REFLEX) CONTROL OF BLOOD PRESSURE (BP)
AND HEART RATE (HR)
The autonomic nervous system regulates BP, HR, and vascular tone to maintain effective perfusion
to vital organs, including during uid shifts with postural change (Figure6.1). Arterial barore‑
ceptors, located in the carotid sinuses and aortic arch, and cardiopulmonary baroreceptors in the
heart and great veins detect changes in arterial BP and central blood volume (e.g., left ventricular
end‑diastolic volume and pressure), respectively.
22,23
Afferent baroreceptor activity is transmitted
to the nucleus tractus solitarius (NTS) in the medulla oblongata of the central nervous system via
the glossopharyngeal (cranial nerve IX) and vagus (cranial nerve X) nerves.
When activated by increased baroreceptor activity (e.g., during increases in BP), the NTS trans‑
mits excitatory glutamatergic signals to the caudal ventrolateral medulla (CVLM), which transmits
inhibitory GABAnergic signals to the rostral ventrolateral medulla (RVLM) thereby inhibiting
the activity of premotor neurons that project to efferent preganglionic sympathetic neurons in
the intermediolateral (IML) region of the thoracolumbar spinal cord. Decreases in central blood
volume, arterial BP, and baroreceptor activity (as occur with standing) evoke the opposite reex
response, an increase in sympathetic nerve activity (SNA). From the IML, preganglionic sympa‑
thetic neurons exit the spinal cord to innervate postganglionic sympathetic neurons that project to
arterial and venous blood vessels, the heart, the adrenal medulla, and other organs.
Increased SNA releases norepinephrine. This binds to cardiac β‑1adrenergic receptors to
increase HR and myocardial contractility and vascular α‑1adrenergic receptors to increase
vascular resistance and decrease venous compliance. Circulating norepinephrine and epineph‑
rine released from the adrenal medulla increase HR and myocardial contractility by binding to
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SYNCOPE
54
cardiac β‑1adrenergic receptors and may cause vasoconstriction or vasodilation by binding to
α‑1 and β‑2 receptors, respectively. Neuropeptide Y released from sympathetic nerves contributes
to
sympathetic‑mediated vasoconstriction.
24
Arterial and cardiopulmonary baroreex‑mediated
increases in vasopressin and renin release (activation of the renin–angiotensin system) also con‑
tribute to the vasoconstrictor response to standing.
23,25
When activated by increased baroreceptor activity, the NTS transmits excitatory glutamatergic
signals to the nucleus ambiguus and dorsal motor nucleus of the vagus, leading to increased para‑
sympathetic nerve activity (paraSNA) to the heart, release of the neurotransmitter acetylcholine
(Ach), binding of Ach to M2muscarinic cholinergic receptors, and decreased HR.
23,25
Therefore,
when central blood volume and arterial BP have decreased withstanding, the baroreex inhibits
cardiac paraSNA and increases HR.
MECHANISMS OF VVS
During vasovagal syncope, disruption in the normal homeostatic mechanisms occurs; the HR
slows, and contractility can become impaired in close association with venous and arteriolar dila‑
tion. Although cerebrovascular autoregulation can compensate to a point, decreased blood ow
to the reticular activating system and other integrating centers in the brain, including the thala‑
mus
26,27
(even for 6–10seconds), results in loss of consciousness.
28
The arterial baroreceptor reex normally prevents or minimizes orthostatic hypotension.
Interestingly, carotid baroreex sensitivity for control of vascular resistance is increased during
60° head‑up tilt in control subjects, underscoring its importance in maintaining BP during ortho‑
static stress.
29
In contrast, this reex was unchanged during head‑up tilt in patients with suspected
prior syncope and documented orthostatic intolerance to lower body negative pressure.
29
The mechanisms that evoke VVS have been investigated and debated for decades. Preclinical
studies have shown that severe hemorrhage and the associated decrease in central blood volume
evoke paradoxical activation of mechanosensitive vagal C‑ber afferents and reex activation of
paraSNA to the heart and reex inhibition of SNA to peripheral blood vessels.
30
Hypercontraction
of an under‑lled left ventricle induced by baroreex‑mediated increases in cardiac SNA and
Figure6.1 Schematic view of autonomic cardiovascular control.
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6A VASOVAGAL SYNCOPE
55
myocardial contractility is thought to cause the paradoxical mechanical activation of vagal affer‑
ents.
31
Similarly, venous pooling of blood during orthostatic stress decreases end‑diastolic volume,
stroke volume, cardiac output, and arterial BP followed by baroreex‑mediated increases in car‑
diac SNA and myocardial contractility. The role of cardiac sensory neurons in syncope has been
challenged. Upright tilt‑induced bradycardia, hypotension, and VVS have been demonstrated in
patients after heart transplant where the heart is denervated.
32
Furthermore, measurements of left
ventricular volume, stroke volume, and ejection fraction in subjects with and without VVS during
upright tilt have supported
33–35
and not supported
36
the hypothesis that mechanical activation of
vagal afferents triggers VVS in humans.
C‑ber vagal afferents innervating the left ventricle are also chemosensitive. Activation of
C‑ber vagal afferents by metabolites, such as prostacyclin, serotonin, bradykinin, protons, and
the TRPV1 agonist capsaicin, also triggers reex inhibition of peripheral SNA, excitation of cardiac
paraSNA, decreased peripheral resistance, decreased HR, and hypotension—referred to as the
Bezold–Jarisch reex.
37
Cardiac C‑ber afferents are often polymodal; metabolites produced in the
heart may sensitize afferent terminals to mechanical stimulation. Interestingly, while activation of
the Bezold–Jarisch reex inhibits peripheral SNA, it exerts both inhibitory and excitatory effects on
cardiac sympathetic nerve activity,
38,39
suggesting the possibility of differential effects on neuronal
subtypes. Activation of the Bezold–Jarisch reex also inhibits arterial baroreex sensitivity via a
central interaction,
40
which may contribute to orthostatic hypotension and VVS. Selective optoge‑
netic activation of cardiac vagal afferent neurons expressing the neuropeptide Y type 2 receptor in
mice evoked the classic Bezold–Jarisch reex: bradycardia, hypotension, and decreased breathing,
accompanied by syncope.
41
Ablation of these neurons abolished the reex.
41
VVS triggered by emotion, anxiety, or pain suggests a central mechanism mediated by
brainstem interactions with higher centers committed to psychological stress and pain sensa‑
tion (e.g., hypothalamus, cerebral cortex). Sensory inputs from peripheral organ systems and
humoral factors may also contribute to the occurrence of VVS. Dynamic sinusoidal stimulation
of the vestibulo‑sympathetic reex induces oscillations in BP and HR and subsequent vasovagal
responses in rats,
42
while habituation of this reex over days suppressed vasovagal responses.
43
Hyperventilation induced by anxiety or emotion will decrease arterial carbon dioxide levels.
The removal of the cerebral vasodilator inuence of CO
2
causes cerebral vasoconstriction that can
provoke syncope.
44
The proinammatory cytokine tumor necrosis factor‑alpha (TNF‑α) elicits
autonomic dysfunction and pathology through multiple effects on vago‑vagal reex circuits in the
brainstem.
45
Epinephrine released from the adrenal medulla during orthostatic stress contributes
to hypotension and syncope via β‑2adrenergic receptor‑mediated vasodilation in skeletal mus‑
cle.
46–48
Multiple mechanisms can contribute to VVS.
There are various central neurological locations that lead to complex sympathetic and para‑
sympathetic nerve processing of the afferent signals. Ironically, tonic vagal activation may inhibit
the vasovagal reex, whereas phasic or rapid parasympathetic activation occurs somewhere after
the onset of the reex to offset transient sympathetic activation. As vasodilation often proceeds
changes in HR and as changes in HR start from a tachycardic response that becomes bradycardic,
the process appears to involve a dynamic between the sympathetic and parasympathetic limbs,
but the link between sympathoinhibition causing vasodilation peripherally and vagal activation
causing bradycardia or asystole remains uncertain.
Manifestations may vary in any given individual and can include bradycardia, asystole, hypo‑
tension, a negative inotropic effect, and cerebral vasoconstriction. Furthermore, once the reex
manifests, mechanisms responsible for its resolution remain unexplored. During the vasovagal
reex, within seconds, there is a corrective response that can take a while to resolve completely
but, nevertheless, prevent serious cerebrovascular repercussions even if asystolic pause and
hypotension persist.
Even for those who are susceptible, the reex is not necessarily reproducible under similar cir‑
cumstances and can change over time. Why younger females and older individuals have a greater
propensity to VVS is uncertain. Further, the vasovagal reex may be life‑threatening in individu‑
als with severe underlying cardiomyopathies as it can be a nal death knell causing asystole in a
patient with end‑stage cardiomyopathy and heart failure.
49
Although heart responses are tightly regulated by various ganglionated plexi located in the
epicardium, locations for the processing and the severity of the processing and specic ganglion‑
ated plexi remain uncertain as to their ability to generate the vasovagal reex. The interaction
between the ganglia and a global vago‑sympathetic response is not well explored. Additionally,
in the nucleus accumbens, nucleus tractus, and nucleus ambiguus, processing that takes place has
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SYNCOPE
56
not been well‑characterized. Regulation between peripheral autonomic reexes and the presence
of loss of consciousness is only associated but, mechanistically, may not necessarily be tied tightly
as central mechanisms may affect loss of consciousness or alterations in consciousness directly
independent of peripheral hemodynamic alterations.
50,51
What has been shown with tilt‑table testing is that there is an early elevation in HR likely due to
sympathetic activation followed by bradycardia and even asystole. This can occur concomitant to
or just after there is intense sympatho‑inhibition as seen by measurements of integrated sympa‑
thetic peroneal nerve trafc.
24
HEMODYNAMIC CHANGES IN VVS
Traditionally, patients with VVS have been categorized into three subtypes depending on
the predominant hemodynamic changes occurring prior to and during the syncopal event.
52
Cardioinhibitory VVS is characterized by a drop in HR, often <30bpm, with periods of asystole
and advanced AV block. A transient increase in parasympathetic activation is thought to drive this
subtype. The vasodepressor subtype is characterized by a drop in systemic arterial pressure irre‑
spective of changes in HR, with SBP often dropping below 60mmHg at the level of the heart. A
transiently decreased peripheral sympathetic tone is thought to drive this subtype. The third sub‑
type, the most common form, is a mixed cardioinhibitory and vasodepressor response. However,
for any individual with a propensity for VVS, there is no reason that one subtype is manifest. On
the contrary, many individuals have one response seen on a loop recorder and a different response
on a tilt‑table test, but there is no reason to suspect that different responses could and do occur
spontaneously.
4
Mechanisms of vasovagal syncope, even in the young, can vary such that some
individuals have reduced vascular resistance versus reduced cardiac output.
53
These subtypes of VVS, often dened by tilt‑table testing, represent an oversimplied and partly
factitious description of VVS. In reality, there is a high degree of inter‑ and intra‑individual vari‑
ability in tilt‑table outcomes,
54
and almost all syncope patients with positive tilt testing demon‑
strate a combination of cardioinhibitory and vasodepressor responses.
55
Furthermore, the specic
response seen on a tilt‑table test does not indicate a specic action. For example, marked asystole
on the tilt‑table does not necessarily require ablation or pacemaker intervention.
56
Nonetheless,
current ESC syncope guidelines still use these denitions to guide therapy.
4
A modern description of VVS summarizes combined cardioinhibitory and vasodepressor
responses in four phases.
55
In phase 1, there is early stability during orthostatic challenges,
such as standing or tilt up. The gravity shift that accompanies standing pushes approximately
500–1,000mL of dedicated cerebral blood volume in the thorax below the diaphragm with most
of the venous pooling within the rst 10seconds of postural change.
57
HR increases may not be
enough to compensate for the decrease in preload and stroke volume, the culmination of which
is a drop in cardiac output by 10%–20%. Systolic blood pressure (SBP) change is variable, but
baroreex‑mediated vasoconstriction causes systemic vascular resistance (SVR) and diastolic
blood pressure (DBP) to increase to maintain mean arterial pressure (MAP).
Phase 2 is characterized by circulatory instability and “presyncope.” A progressive increase in
SVR reduces cardiac output with an eventual drop in SBP by about 20mmHg on average. Cerebral
blood volume is mildly reduced due mostly to a drop in MAP and cerebrovascular constriction to
a lesser extent.
39
Phase 3 is characterized by terminal hypotension and syncope. Reduced brainstem perfu‑
sion is rapid with a fall in SBP by about 50mmHg on average over the nal 30–60seconds before
syncope. MAP and HR decrease, with simultaneous symptoms of autonomic activation includ‑
ing warmth and nausea. A fall in HR occurs after a fall in MAP. The fall in MAP is attributed to
decreased cardiac output (35%–48% from baseline) rather than decreased vascular tone, as SVR
appears to be increased throughout phase three.
Phase 4 is the recovery phase, when the table is tilted to its horizontal starting position. In this
phase, there is a rapid improvement in venous return, an increase in preload, and an increase in
cardiac output. MAP recovers within 30seconds and may temporarily elevate above the starting
MAP. HR rapidly recovers to baseline.
55
NEUROHORMONAL INVOLVEMENT IN VVS
Neurohormonal shifts occur during VVS, but the mechanistic relationship to VVS is unknown.
39
A notable early rise in circulating epinephrine occurs before syncope during tilt testing, reaching
values of 6–16 times baseline,
11
whereas those who do not have VVS on tilt testing have a more
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6A VASOVAGAL SYNCOPE
57
marked elevation in norepinephrine. Elevated urinary epinephrine levels are present in blood
donors who experienced syncope during donation compared to those who did not experience
syncope with blood donation.
48
A trend toward norepinephrine elevations immediately preceding
syncope is less consistent. A disproportionate rise in epinephrine over norepinephrine during tilt
testing appears to predict patients who will experience VVS.
47
Adenosine is proposed as a regulator of VVS.
58
In addition to its well‑known inhibitory cardio‑
vascular actions, adenosine has a sympathoexcitatory effect mediated via baroreex, similar to iso‑
proterenol, which may feed into the aforementioned autonomic cascade.
59
Theophylline has been
considered a therapy for this subset of patients with syncope, but data are limited.
Additional hormone shifts studied in the context of VVS include arginine vasopressin, adreno‑
medullin, atrial and brain natriuretic peptides, endothelin‑1, and opioids.
11,13,60,61
Nonetheless, it is
currently uncertain whether these various agents collectively or individually directly impact the
pathophysiology of VVS or if they primarily represent a compensatory reaction to a developing
hemodynamic shift.
SYMPATHETIC AND PARASYMPATHETIC ACTIVITY IN VVS
Muscle sympathetic nerve activity (MSNA) can be recorded from the peroneal nerve using
microneurography alongside hemodynamic measurements during tilt testing to directly measure
beat‑to‑beat changes in MSNA, BP, and HR throughout the phases of VVS. Enhanced MSNA cor‑
relates well with increases in DBP due to sympathetic‑mediated vasoconstriction in non‑syncopal
patients,
24
but the opposite occurs during VVS.
The autonomic progression of VVS occurs in stages following the transition from supine
to head‑up positioning on tilt testing.
24,62,63
During the rst few minutes of head‑up tilt,
baroreex‑mediated increases in HR, MSNA, and peripheral vascular resistance maintain BP.
Interestingly, these changes are accompanied by increases in the amplitude of low‑frequency
(LF, ~0.1Hz) oscillations of MSNA and BP and a decrease in the amplitude of high‑frequency (HF)
oscillations of HR (pulse interval) in phase with breathing.
24,62,63
The decrease in HF‑HR variabil‑
ity reects decreased paraSNA in the heart. Continued venous pooling of blood and decreases in
left ventricular stroke volume and cardiac output lead to a slow decrease in BP accompanied by
decreases in the amplitude of LF‑MSNA oscillations despite continued elevation in mean MSNA
and LF‑BP variability.
62
Subjects destined to faint demonstrate further decreases in LF‑MSNA
oscillations followed by sudden cessation of MSNA and marked decreases in HR and BP
(presyncope) prior to syncope.
24,50,62,63
The mechanisms that cause orthostatic hypotension and
rapid conversion from cardiac sympathetic to parasympathetic dominance at syncope include (1)
loss of baroreceptor reex sensitivity; (2) activation of left ventricular vagal afferent C‑bers by
hypercontraction of the under‑lled ventricle (as evoked by increased cardiac SNA) and/or chemi‑
cal factors generated in the stressed heart; (3) sensory inputs from other organs (e.g., gut, bladder,
kidney, vestibular system); and (4) central nervous system mechanisms invoked by psychological
stress, emotion, or pain.
E VA LUAT I ON
The differential diagnosis for syncope is broad. Many conditions mimic syncope. On the differen‑
tial are cardiac (non‑autonomically mediated) syncope and orthostatic hypotension. Neurogenic
orthostatic hypotension is often conated with VVS. However, these can be differentiated based
on hemodynamic response to tilt testing.
64,65
Non‑syncopal episodes can also be confused for VVS,
including seizures, hypoglycemia, chemical intoxication, narcolepsy, psychogenic pseudosyncope,
and orthopedic falls.
Tilt testing can diagnose and assess conditions including reex syncope, autonomic failure,
delayed orthostatic hypotension, and postural orthostatic tachycardia syndrome and distinguish
syncope from psychogenic pseudosyncope. While it has limited value in evaluating treatment
effectiveness,
66
it can demonstrate susceptibility to reex syncope and indicate when to initiate
treatment. The specicity of tilt testing is limited in diagnosing reex syncope, however.
67, 68
While
92% of VVS patients show a positive tilt‑test result, 47% of those with arrhythmic syncope also
exhibit a positive tilt test.
6
Furthermore, the introduction of pharmacological provocation (such as sublingual nitroglyc‑
erin or isoproterenol) raises the risk of inducing syncope during tilt testing, even in individuals
who have never experienced a syncopal episode.
4,69
While a negative tilt‑table response does not
exclude a diagnosis of reex syncope, a positive test does not necessarily indicate the cause for
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