REVIEW
Europace (2009) 11, 414–420
doi:10.1093/europace/eun387
Genetic aspects of vasovagal syncope: a
systematic review of current evidence
Louise R.A. Olde Nordkamp 1, Wouter Wieling 1, Aeilko H. Zwinderman 2,
Arthur A.M. Wilde 3, and Nynke van Dijk 2*
1
Department of Internal Medicine, Academic Medical Centre, Amsterdam, The Netherlands; 2Department of Clinical Epidemiology Biostatistics and Bioinformatics,
Academic Medical Centre, PO Box 22700, 1100 DE Amsterdam, The Netherlands; and 3Department of Cardiology, Academic Medical Centre, Amsterdam,
The Netherlands
Received 2 September 2008; accepted after revision 22 December 2008; online publish-ahead-of-print 18 January 2009
Knowledge on the aetiology of vasovagal syncope (VVS) is of great importance to optimize its diagnostic and therapeutic options. To unravel
the largely unknown pathophysiology, studies on genetic aspects of VVS can be of use. This systematic review on all available literature aims
to provide an overview of the current knowledge of VVS genetics. The MEDLINE and EMBASE database were systematically searched for all
studies discussing genetic factors as a cause of VVS. Hereditary aspects of VVS were studied in 19 studies. Six studies determined a positive
family history in, respectively, 19 –90% of the VVS patients. These numbers, however, are not higher than the cumulative incidence of VVS in
the general population (35–39%). Four studies examined potential genetic polymorphisms associated with VVS. Only a Gly389 allele was
more frequently present in VVS patients with a positive HUT test, although the significance level was set much higher than usual in
genetic studies, and this result has not been replicated so far. Knowledge on genetic aspects of VVS could be very useful in clinical practice
and research, but the current evidence that it has a genetic basis is not very strong.
----------------------------------------------------------------------------------------------------------------------------------------------------------Keywords
Syncope † Vasovagal syncope † Genetics † Family history † Twins
Introduction
Vasovagal syncope (VVS) is transient loss of consciousness due to a
sudden drop of blood pressure (BP) caused by reflex peripheral
vasodilatation combined with bradycardia.1 Vasovagal syncope is
a common condition in the general population. The lifetime
cumulative incidence in subjects up to 65 years is 35– 39%.2,3
Vasovagal syncope reduces the quality of life of patients significantly,
particularly in patients with recurrent episodes.4,5 Mortality rate
for VVS is almost zero,6 but it can be misinterpreted for
more dangerous conditions, like cardiac syncope,6 and result in dangerous situations, like when driving.7 To optimize the diagnostic and
therapeutic options for VVS, knowledge of its aetiology is important.
To unravel the largely unknown pathophysiology,8 studies on the
genetic basis of VVS could be useful. These studies could also be of
importance for developing new diagnostic methods,9,10 overcoming
classification difficulties by more accurate classification of syncope,
finding new therapy targets, and predicting therapy responses.
Determining the role of genetic factors might also lead to a better
understanding of the influence of environmental factors in VVS10
and why VVS is more frequent in women than in men2,11 and in
white people than in black people.12 In this study, we systematically
review the available literature on VVS genetics and provide an overview of current knowledge.
Methods
Search strategies and extraction
of relevant results
We searched the MEDLINE database (Pubmed; 1950 to 19 November
2007) and the EMBASE database (Ovid; 1988 to 19 November 2007),
using the search terms described in Table 1. We also searched on 3
December 2007 the Dutch Trial Register (www.trialregister.nl), the
trial register of the National Institute of Health (www.clinicaltrials.gov),
and the metaRegister of Controlled Trials (www.controlled-trials.com),
using the search term ‘syncope’ for ongoing studies on this subject.
Criteria for inclusion of studies
For this systematic review, we considered all studies discussing genetic
factors as a cause of VVS. Vasovagal syncope was defined as transient
loss of consciousness due to reflex vasodilatation and/or bradycardia,
resulting in a sudden drop in BP. It can be provoked by stressors
such as strong emotions or prolonged standing. The diagnosis of
* Corresponding author. Tel: þ31 20 5668975, Fax: þ31 20 6912683, Email: [email protected]
Published on behalf of the European Society of Cardiology. All rights reserved. & The Author 2009. For permissions please email: [email protected].
415
Genetic aspects of VVS
Table 1 Search terms used for the MEDLINE and EMBASE database
MEDLINE (Pubmed): 1950 to 19 November 2007
..............................................................................................................................................................................
((‘Genetics’[Mesh]) OR (‘Histocompatibility Testing’[Mesh]) OR (‘Genetic Processes’[Mesh]) OR (‘Genetic Phenomena’[Mesh]) OR (‘Genetic
Structures’[Mesh]) OR (‘genetics’[Subheading]) OR (‘Heredity’[Mesh]) OR (heredit*) OR (‘Siblings’[Mesh] OR ‘Twin Studies’[Mesh]) OR
(‘Family’[Mesh]) OR (‘Pedigree’[Mesh]) OR (Genealogic Tree*) OR (Family Tree*) OR ((‘Twins’[Mesh] OR ‘Twin Studies’[Mesh] OR ‘Twin Study
‘[Publication Type]) OR (‘Multiple Birth Offspring’[Mesh] OR ‘Genetics, Medical’[Mesh])))
AND
((((‘syncope’[MeSH Terms] OR syncope[Text Word]) OR (syncope*) OR (vasovagal syncope*) OR (faint*) OR (Syncopal Episode*) OR (Syncopal
Vertigo) OR (Cardiogenic Syncope*) OR (Carotid Sinus Syncope*) OR (Effort Syncope*) OR (Situational Syncope*) OR (Tussive Syncope*) OR
(neurally mediated syncope) OR (postural syncope*) OR (Micturition Syncope*) OR (Drop Attack*))) OR ((collapse*)))
AND
((Humans[Mesh]) AND (English[lang] OR Dutch[lang]))
EMBASE (OVID): 1988 to 19 November 2007
..............................................................................................................................................................................
(exp genetics/) OR (histocompatibility test/) OR (exp heredity/) OR (genetic variability/) OR (heredit$.mp. [mp¼title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]) OR (Siblings.mp. [mp¼title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]) OR (siblings$.mp.) OR (exp Twins/) OR (twin studies.mp.) OR (exp
family/) OR (exp genetic analysis/ or pedigree analysis/) OR (Genealogic Tree$.mp.) OR (Family Tree$.mp. [mp¼title, abstract, subject headings, heading
word, drug trade name, original title, device manufacturer, drug manufacturer name]) OR (exp Multiple Pregnancy/) OR (exp medical genetics/)
AND
(exp unconsciousness/) OR (syncope$.mp. [mp ¼ title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug
manufacturer name]) OR (SYNCOPE/ or HEAT SYNCOPE/) OR (vasovagal syncope$.mp.) OR (faint$.mp. [mp ¼ title, abstract, subject headings,
heading word, drug trade name, original title, device manufacturer, drug manufacturer name]) OR (Syncopal Episode$.mp. [mp ¼ title, abstract, subject
headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name]) OR (Cardiogenic Syncope.mp.) OR (carotid
sinus syncope/ or Carotid Sinus Syncope.mp.) OR (Effort Syncope.mp.) OR (Situational Syncope.mp.) OR (Tussive Syncope.mp.) OR (neurally
mediated syncope.mp.) OR (postural syncope.mp.) OR (micturition syncope/ or Micturition Syncope.mp.) OR (Drop Attack.mp. or Drop Attack/) OR
(collapse$.mp. [mp ¼ title, abstract, subject headings, heading word, drug trade name, original title, device manufacturer, drug manufacturer name])
AND
Limit to (human AND (dutch OR english))
VVS is made based on typical history, head-up tilt (HUT) testing, or a
combination of both.1
We considered all types of studies, involving human participants
of any age group and of either sex. All study designs and various
outcomes were considered. They included: studies with descriptive
information on families with VVS; studies with quantitative measures
of the number of relatives with VVS in fainting and non-fainting
subjects; familial studies with haemodynamic measures during stress;
studies determining the prevalence of specific genetic polymorphisms
in subjects with and without VVS; and studies calculating the impact
of genetic polymorphisms on VVS.
Two authors (L.R.A.O.N. and N.D.) independently reviewed the
titles of the retrieved studies for eligibility. Studies with titles describing
unrelated diseases, sudden death of participants, non-human participants, or in vitro research were excluded. Disagreements between
the two authors regarding a study’s eligibility were resolved by discussion or, where necessary, by a third person (W.W.).
Of the eligible studies the abstracts, or if necessary, the paper was
read. A study was included if human participants with VVS were
studied and if the topic was familial VVS or genetics of VVS.
Secondly, the search was extended by searching the references
of the obtained papers for relevant studies that fitted the inclusion
criteria. Only articles written in English and Dutch were used.
Methodological quality
The quality/credibility of genetic association studies was assessed
using the guidelines of Ioannidis et al.13 In these guidelines, a semiquantitative index is calculated on the basis of three pillars. The first
pillar is the amount of evidence, which ensures that studies with a
larger amount of evidence provide more statistical power for a presumed association. The second pillar is the extent of replication,
which counteracts inconsistencies between studies such as statistical
considerations and also epidemiological considerations for the standardization or at least harmonization of phenotyping, genotyping and
analytical models across studies. The third pillar is the protection
from biases, which contains a consideration of biases in phenotype
definition, biases in genotyping, population stratification, and, for
meta-analysis only, selective reporting biases.
Two authors (L.R.A.O.N. and N.D.) assessed all included association
studies independently on the three pillars. Thereafter, they labelled
studies as ‘strong’, ‘moderate’, or ‘weak’ epidemiological credibility.
Disagreements on the study’s credibility were resolved by discussion
or, where necessary, by a third person (A.H.Z.).
Data extraction
Two authors (L.R.A.O.N. and N.D.) examined the results of the
included studies and extracted the results for this review independently. Disagreements between the authors regarding the results
were resolved by discussion resulting in consensus or, where necessary, a third person (W.W.).
Results
Selection of studies
The MEDLINE and the EMBASE search yielded 2021 and 2109
results, respectively. None of the studies in the trial registers
416
Table 2 Overview of the included studies
Report
Study design
Study population
Number of
participants
Mean
age
(SD)
Female
(%)
Main resulta
.............................................................................................................................................................................................................................................
Case report
70-year-old female index patient with
recurrent VVS with complete AV
block during syncopal episode
1
36-year-old daughter also reported syncope with a transient complete AV block during
a syncopal episode
Cooper et al. 18
Case report
1
Mother also reported recurrent syncope
Mathias et al. 21
Case report
19-year-old female index patient
reporting recurrent VVS
11-year-old female index patient with
recurrent VVS, started at the age of
2.5
1
Paternal grandmother, father, and three of five siblings also reported VVS; none of the
adopted siblings reported VVS
Newton et al.24
Case report
10-year-old index patient (unknown
gender) with recurrent syncope
1
Sibling, father, paternal grandfather, brother and sister of paternal grandfather, paternal
uncle, and child of paternal uncle also reported syncope or pre-syncope
Marquez
et al.26
Case–series
20-year-old female index patient with
recurrent VVS; two sets of
monozygotic twins all report
recurrent VVS
5
Siblings and father of 20-year-old female also reported recurrent syncope; mother of
monozygotic twin sisters also reported recurrent syncope
Kleinknecht
and Lenz15
Case–control
Psychology and sociology students
volunteers
204
n/a
63
66% of blood-injury-related fainting students report at least one parent with a history
of blood-injury-related fainting vs. 41% of non-fainting students
Kleinknecht
et al.16
Case–control
Psychology and sociology students
volunteers with a history of blood
injury fainting
103
n/a
76
94% of the essential fainters (¼ non-anxious blood-injury-related fainters) report a
parental history of fainting
Camfield and
Camfield17
Case–control
Outpatient visitors of paediatric
neurologist with history of VVS
30
10
73
90% of fainting children report at least one relative with a history of fainting vs. 33% of
non-fainting best friends
Mathias et al.22
Case–control
Patients with recurrent syncope and
pre-syncope referred to a specialized
autonomic unit
641
46
58
Positive family history in 36% of patients with VVS
Lucas et al. 28
Case–control
Fatigued Gulf war veterans
49
n/a
n/a
Fatigued veterans with VVS had equal or less frequent positive family history on VVS
than fatigued veterans without VVS.
Mathias et al. 20
Cohort study
Patients with VVS referred to specialized
autonomic unit
119
34.4
65
Familial history of syncope in 37% of the VVS patients (positive HUT patients 51 vs.
28% in negative HUT patients)
Newton et al. 23
Cohort study
HUT-positive VVS patients at the third
line cardiovascular investigation unit
441
n/a
n/a
A family history of syncope was found in 19% of the VVS patients
Serletis et al.27
Cohort study
Medical students and their family
290
39 (16)
51
A student with two fainting parents was more likely to faint than the one with no
fainting parents; offspring of either sex whose mother faints were more likely to faint
than those whose mother does not faint; having a father who faints significantly
increases the risk of VVS in sons, but not in daughters
Newton et al.25
Case–control
HUT-positive VVS patients at the third
line cardiovascular investigation unit
165
56 (19)
62
The frequency of ACE insertion –deletion polymorphisms is not higher in subjects with
VVS than in the general population. A family history of syncope was found in 23% of
the the VVS patients
Marquez
et al. 30
Case–control
Patients with unexplained syncope who
underwent a HUT test
50
27.9
58
The Gly389 allele frequency in positive HUT patients was 30 vs. 3% in the negative
HUT group (P ¼ 0.012)
L.R.A. Olde Nordkamp et al.
Talwar et al.14
417
Time to pre-syncope during HUT was similar in twin pairs; haemodynamic variables
were moderately related and became less similar as the level of orthostatic stress
increased
(154 hits) were applicable to our study. Therefore, with the
removal of duplicate studies, 3325 titles were screened. Of
these, 82 were eligible and 19 fulfilled all inclusion criteria and
were included14 – 32 in this review.
An overview of the selected studies is displayed in Table 2. Four
studies were case reports,14,18,21,24 one was a case series,26 five
were cohort studies,19,20,23,27,29 and nine were case –control
studies.15 – 17,22,25,28,30 – 32
Quality of studies
Overall, the epidemiological evidence of the association studies is
weak. In most studies, the sample size was smaller than 100 subjects. There were demonstrable inconsistencies between the
included studies and a meta-analysis has not been performed yet.
Finally, the phenotype definition was varying across studies, the
populations were often from different descent, and, if appropriate,
genotyping quality was not examined.
27 (7)
50
Interpretation of results
Cohort study
O’Leary et al.29
VVS, vasovagal syncope; HUT, head-up tilt test; n/a, result not available.
a
Relevant results for this review.
32
Cohort study
Page and
Martin19
Monozygotic twin pair volunteers
1318
45.2
(11.2)
66
Increased expression and up-regulation of A2A adenosine receptors in patients with a
positive HUT test. Receptor affinity for adenosine and the relative amount mRNA
(receptor synthesis) were similar in both patients with a positive and negative HUT
test
Non-blood-injury fainting is best explained by a model assuming shared and unique
environmental variables. Blood fainting was best explained by a model assuming
unique environmental plus additive genetic and/or shared environmental variables
48
49.6 (3)
33
Case–control
Carrega et al. 32
Patients referred to university hospital
with two or more unexplained
episodes of pre-syncope/syncope in
the preceding year
Twin pairs volunteering to supply blood
for biochemical and DNA analysis
Case–control
Lelonek et al.31
Patients with recurrent syncope (more
than two episodes in the last 3
months) with a positive HUT test
68
35.7 (20)
79
The frequency of the GNB3 825C allele was higher in patients with a typical vasovagal
history than in those without a typical vasovagal history
Genetic aspects of VVS
The studies on familial VVS suggest a genetic component for VVS
by describing recurrent syncope in VVS patients and in relatives
with the same symptoms. The frequency of a positive family
history in VVS patients ranged from 1923 to 90%17 in different
studies (Figure 1). Two studies compared the frequency of a
positive family history of VVS patients to non-VVS patients,
both demonstrating a significant difference (9017 and 66%15 in
VVS patients vs. 3317 and 41%15 in non-VVS patients). A positive
family history most often concerned an affected child or
parent.17,20
Serletis et al.27 calculated the risk on VVS in subjects with syncopal parents in 62 medical students and 228 first-degree relatives.
Offspring with two fainting parents were more likely to faint (65%)
than those with no fainting parents (23%), but offspring with one
fainting parent were not significantly more likely (39%) to faint
than those with no fainting parents. Offspring of either sex
whose mother fainted were more likely to faint than those
whose mother did not faint. Fainting fathers increased the risk of
syncope only in their sons, not in their daughters.27
Figure 1 Literature overview in proportion of positive fainting
family history in fainting and non-fainting offspring.
418
On the contrary, Lucas et al.28 demonstrated that a family
history of fainting was not a risk factor for neurally mediated hypotension in chronically fatigued Gulf War veterans. The frequency of
a positive family history in women was even higher in the control
group than in the VVS patients (41 vs. 12%; P , 0.01).
Three studies demonstrate the possible presence of genetic
mechanisms of VVS. O’Leary et al.29 demonstrated that the
capacity to deal with orthostatic stress appears to be similar in
16 monozygotic twin pairs, but the haemodynamic variables
were only moderately related, suggesting the mechanism(s) by
which the orthostatic tolerance was achieved varied. Kleinknecht
et al.16 reported that their group of 103 fainters mostly existed
of non-blood-injury-injection fainters (fainting not induced by
blood phobia). Of this group of non-blood-injury-injection fainters,
94% reported a positive parental fainting history, in contrast to
56% of the blood-injury-injection fainters, suggesting different
types of fainting. Page and Martin19 took environmental factors
into account next to genetic factors and the type of fainting.
They demonstrated that non-blood-injury fainting is best explained
by a model only assuming shared and unique environmental variables. Blood-injury-injection fainting was best explained by a
model assuming unique environmental plus additive genetic and/
or shared environmental variables, suggesting a possible genetic
factor only for patients with blood-injury-induced fainting and
not for other forms of VVS.
Four studies examined the influence of specific polymorphisms
on the risk of VVS. Newton et al.25 examined the influence of
angiotensin-converting enzyme insertion/deletion polymorphisms,
which could lead to altered circulating angiotensin levels.
Carrega et al.32 examined whether adenosine A2A receptor
expression, which acts on blood vessel tone and sinoatrial node,
is altered in patients with VVS. Lelonek et al.31 studied the frequency of GNB3 C825T polymorphisms, enhancing vascular reactivity in HUT-positive patients with and without a typical vasovagal
history, and Márquez et al.30 studied the Gly389 allele frequency,
which leads to a lower contractile responsiveness to catecholamines and therefore dysregulates the autonomic nervous
system. Only the Gly389 allele polymorphism was more frequently
present in VVS patients with a positive HUT test than in HUTnegative subjects.30 None of the other studies showed a difference
in the presence of the studied polymorphisms between patients
with VVS and subjects without VVS.
Discussion
This systematic review included all available studies on genetic
aspects of VVS, including case reports to provide a complete overview of the available evidence. Hereditary aspects of VVS were
described in 19 studies. Five case reports described possible familial clustering of VVS.14,18,21,24,26 Six other studies15,17,20,22,23,25
determined a positive family history in, respectively, 19% to even
90% of the VVS patients. These numbers, however, are not
higher than the cumulative incidence of VVS in the general
population (35 –39%).2,3,11,27,33,34 In fact, if a family consists of
three family members (e.g. two parents, one sibling) and the
prevalence of VVS in the general population is roughly 37%, the
chance of an episode of VVS in one of the three members is
L.R.A. Olde Nordkamp et al.
75% (12[1 2 0.37]3 ¼ 0.75). One study28 found no difference
between family members of VVS patients compared to persons
without VVS. The study of Serletis et al.27 described that a fainting
mother increased the risk of VVS in either sex, whereas a fainting
father only increased the risk in sons. This observation is rather
doubtful in terms of causal genetic nature, since VVS more often
occurs in females in the general population.
The number of studies and amount of evidence provided is low,
especially the number of genetic association studies is low. Four
studies examined potential genetic polymorphisms associated
with VVS. Only a Gly389 allele was more frequently present in
VVS patients with a positive HUT test30 (P ¼ 0.012). Although
this is a statistically significant result when considering a P-value
of ,0.05 significant, in genetic studies the significance level is
usually set much lower and the results have not been replicated
so far,13 resulting in a very low level of evidence. Although
genetic influences on the occurrence of VVS episodes seem plausible, nurture effects have not been excluded19 and specific high-risk
polymorphisms have not been identified so far. Differences in
vasovagal responses between subjects16 and different mechanisms
for the development of orthostatic intolerance29 suggest that
various genetic polymorphisms could be of significance.
Several other issues hamper successful research on the genetics
of VVS. Vasovagal syncope is ill-defined, and researchers disagree
on the reference standard for VVS. Some studies only include
patients with a positive HUT test,18,20,23 – 26,28 – 30 others use
score lists27 and interviews15,16 or only history and physical examination17,19 – 23,32,35 to verify their diagnosis. Study populations also
vary in the number of VVS episodes experienced and age. Some
studies18,21,22,24,26,30 – 32 only include patients with recurrent syncopal episodes, whereas other studies15 – 17,19,27 also include patients
who experienced only one episode of VVS. Considering that up to
40% of the population experiences one or more syncopal episodes
during their lives, and this cumulative incidence rises with age, one
could discuss when the phenotype ‘vasovagal patient’ should be
considered present. These differences in definitions and study
populations make it difficult to compare studies and impossible
when aiming to pool results. Uniform phenotyping is mandatory
for successful genotyping.
Additionally, it is known that in many patients with VVS, episodes are triggered by specific environmental triggers such as
fear or orthostasis.36 Differences in vasovagal responses between
patients with different triggers could be an indication of different
pathogenetic pathways involved and thus different genes and
genetic markers.
Another difficulty resulting from the high incidence of VVS is
that it can occur next to other diseases or syndromes and could
therefore easily be misdiagnosed and linked with genetic polymorphisms of other diseases or syndromes.37
Vasovagal syncope is probably multifactorial, because blockade
of individual pathways does not prevent VVS.38,39 It is also unlikely
that VVS is caused by single causal mutations. Different sets of
genes in combination with environmental triggers can possibly
lower a threshold, which leads to an increased risk to develop a
vasovagal episode.
There are multiple potential targets for genetic polymorphisms
causing increased risk of VVS.40 Alterations in the water and salt
419
Genetic aspects of VVS
regulation, such as the renin –angiotensin –aldosterone system, can
cause a slight hypovolaemia, which possibly lowers the threshold
for VVS.41 Another target can be a reduced level of creatine
kinase, leading to reduced potential for vasoconstriction to counteract a sudden drop in BP.42 Additionally, other known regulators
of peripheral resistance, such as the arginine vasopressin cascade,43
b2-adrenergic receptors, human urotensine-II,44 and nitric monooxide cascade,45 or regulators of the sympathetic nerve activity,
can also be targets in which genetic polymorphisms can lead to
a lower threshold for VVS.46 Known regulators of the heart rate,
such as regulators of the vagus nerve (familial vagotonia is
described47) or baroreceptors and regulators of the stroke
volume, are additional options.46
One study in this review27 showed that fainting fathers only
increase the risk in sons, not in daughters. On the contrary, VVS
is in general more common in women. These sex differences
are still not fully understood. Perhaps hormonal factors are of
influence in triggering VVS.48
Identification of gene variants that protect people from VVS or
gene variants associated with diseases with a possible common
mechanism, such as motion sickness,49 can lead to understanding
VVS genetics. Related disorders such as orthostatic intolerance,
postural tachycardia syndrome, or hypertension may have the
same genetic basis or reveal a protective mechanism. Therefore,
genetic research in these disorders can lead to potential
targets50 – 55 for VVS research. For example, Ditto et al.35 found
that inexperienced donors without a parental history of hypertension had a larger tendency to faint than inexperienced donors
with a parental history of hypertension or experienced donors.
Assuming a genetic basis for hypertension, this study suggests
hypertension is protective of VVS and BP regulatory genes could
be oppositely affected in VVS and hypertension.
Additionally, pharmacological agents with hypotensive adverse
effects, such as MAO inhibitors,56 can elucidate gene variants of VVS.
Although there are many potential targets for a genetic basis
of VVS, environmental factors certainly contribute to the development of episodes in some subjects. Morris et al.57 and Blount
et al.58 revealed that children’s frequency of syncope with a
positive and negative HUT test was associated with parental psychological functioning. They also demonstrated that syncopal episodes
were more frequent in children living in families with stepfathers
than those living with biological fathers, suggesting an important
role of parents’ psychological stress on children’s syncope.
In 1966, Moss and McEvedy59 already described a faint epidemic
among girls at a secondary school, which was considered to be
due to mass hysteria. Combined with the fact that relatives share
not only their genetic basis but also their environment, familial
clustering of VVS alone, if present, does therefore not prove a
genetic basis.
Page and Martin.19 demonstrated that multiple genetic and
environmental factors act together in the development of VVS.
These factors overlap and therefore hamper research, so structural
and step-by-step examination is necessary. Until now, not much is
known about the genetics of VVS. To examine a potential genetic
influence on VVS, we therefore have to answer the following main
questions: (i) Is there familial clustering or correlation? (ii) Is there a
genetic component in this clustering or correlation? (iii) According
to what model inherits VVS? (iv) Which genes are involved? (v)
What is the functional effect of the associated mutations? (vi)
What is the significance of the mutation in the population?60
Until now, mostly familial clustering and correlation of VVS is
studied, suggesting, but not proving, a familial clustering or
correlation. Since VVS is a very common condition in the
general population,2,3,11,27,33,34 the question arises whether this
clustering can be explained by the high prevalence and/or environmental factors. Clarification on this part using twin-adoption and
migration research enables evaluating the impact of genotype
and environmental factors and segregation analysis to determine
the model of heritage. Alternatively, large families in which VVS
seems highly frequent can be used for classical linkage analysis,
providing a potential shortcut to causal genes.
Conclusion
The evidence that VVS has a genetic basis is not very strong.
Research is hampered by the absence of necessary conditions,
such as a uniform definition of VVS and the high prevalence in
the general population. However, knowledge on genetic aspects
of VVS seems interesting and many potential future studies are
possible.
Conflict of interest: none declared.
Funding
All authors are employees of the Academic Medical Center. No
external funding was received for this study.
References
1. Brignole M, Alboni P, Benditt DG, Bergfeldt L, Blanc JJ, Bloch Thomson PE et al.
Guidelines on management (diagnosis and treatment) of syncope—update 2004.
Europace 2004;6:467 –537.
2. Ganzeboom KS, Mairuhu G, Reitsma JB, Linzer M, Wieling W, van Dijk N. Lifetime
cumulative incidence of syncope in the general population: a study of 549 Dutch
subjects aged 35 –60 years. J Cardiovasc Electrophysiol 2006;17:1172 –6.
3. Sheldon RS, Sheldon AG, Connolly SJ, Morillo CA, Klingenheben T, Krahn AD
et al. Age of first faint in patients with vasovagal syncope. J Cardiovasc Electrophysiol
2006;17:49 –54.
4. van Dijk N, Sprangers MA, Boer KR, Colman N, Wieling W, Linzer M. Quality of
life within one year following presentation after transient loss of consciousness.
Am J Cardiol 2007;100:672 –6.
5. Rose MS, Koshman ML, Spreng S, Sheldon R. The relationship between
health-related quality of life and frequency of spells in patients with syncope.
J Clin Epidemiol 2000;53:1209 –16.
6. Kapoor WN. Syncope. N Engl J Med 2000;343:1856 – 62.
7. Li H, Weitzel M, Easley A, Barrington W, Windle J. Potential risk of vasovagal
syncope for motor vehicle driving. Am J Cardiol 2000;85:184 – 6.
8. van Dijk JG. In a sweat over the riddle of reflex syncope. Clin Auton Res 2004;14:
212 –3.
9. Drell D, Adamson A. Fast Forward to 2020: What to Expect in Molecular Medicine.
http://www.ornl.gov/sci/techresources/Human_Genome/medicine/tnty.shtml (31
August 2008, date last accessed).
10. Collins FS, Green ED, Guttmacher AE, Guyer MS. A vision for the future of
genomics research. Nature 2003;422:835 –47.
11. Ganzeboom KS, Colman N, Reitsma JB, Shen WK, Wieling W. Prevalence and
triggers of syncope in medical students. Am J Cardiol 2003;91:1006 –8, A8.
12. Newman BH. Vasovagal reactions in high school students: findings relative to race,
risk factor synergism, female sex, and non-high school participants. Transfusion
2002;42:1557 – 60.
13. Ioannidis JP, Boffetta P, Little J, O’Brian TR, Uitterlinden AG, Vineis P et al.
Assessment of cumulative evidence on genetic associations: interim guidelines.
Int J Epidemiol 2008;37:120 –32.
420
14. Talwar KK, Edvardsson N, Varnauskas E. Paroxysmal vagally mediated AV block
with recurrent syncope. Clin Cardiol 1985;8:337–40.
15. Kleinknecht RA, Lenz J. Blood/injury fear, fainting and avoidance of
medically-related situations: a family correspondence study. Behav Res Ther
1989;27:537 –47.
16. Kleinknecht RA, Lenz J, Ford G, DeBerard S. Types and correlates of blood/
injury-related vasovagal syncope. Behav Res Ther 1990;28:289 –95.
17. Camfield PR, Camfield CS. Syncope in childhood: a case control clinical study of
the familial tendency to faint. Can J Neurol Sci 1990;17:306 –8.
18. Cooper CJ, Ridker P, Shea J, Creager MA. Familial occurrence of neurocardiogenic syncope. N Engl J Med 1994;331:205.
19. Page AC, Martin NG. Testing a genetic structure of blood-injury-injection fears.
Am J Med Genet 1998;81:377 –84.
20. Mathias CJ, Deguchi K, Bleasdale-Barr K, Kimber JR. Frequency of family history in
vasovagal syncope. Lancet 1998;352:33 –4.
21. Mathias CJ, Deguchi K, Bleasdale-Barr K, Smith S. Familial vasovagal syncope and
pseudosyncope: observations in a case with both natural and adopted siblings.
Clin Auton Res 2000;10:43 –5.
22. Mathias CJ, Deguchi K, Schatz I. Observations on recurrent syncope and
presyncope in 641 patients. Lancet 2001;357:348 –53.
23. Newton JL, Kenny R, Lawson J, Frearson R, Donaldson P. Prevalence of family
history in vasovagal syncope and haemodynamic response to head up tilt in
first degree relatives: preliminary data for the Newcastle cohort. Clin Auton Res
2003;13:22 –6.
24. Newton JL, Kerr S, Pairman J, McLaren A, Norton M, Kenny RA et al. Familial
neurocardiogenic (vasovagal) syncope. Am J Med Genet A 2005;133:176–9.
25. Newton JL, Donaldson P, Parry S, Kenny RA, Smith J, Gibson AM et al.
Angiotensin converting enzyme insertion/deletion polymorphisms in vasovagal
syncope. Europace 2005;7:396 –9.
26. Marquez MF, Urias KI, Hermosillo AG, Jardon JL, Iturralde P, Colin L et al. Familial
vasovagal syncope. Europace 2005;7:472 –4.
27. Serletis A, Rose S, Sheldon AG, Sheldon RS. Vasovagal syncope in medical
students and their first-degree relatives. Eur Heart J 2006;27:1965 –70.
28. Lucas KE, Armenian HK, Petersen GM, Rowe PC. Familial aggregation of fainting
in a case-control study of neurally mediated hypotension patients who present
with unexplained chronic fatigue. Europace 2006;8:846 – 51.
29. O’Leary DD, Hughson RL, Shoemaker JK, Greaves DK, Watenpaugh DE,
Macias BR et al. Heterogeneity of responses to orthostatic stress in homozygous
twins. J Appl Physiol 2007;102:249 –54.
30. Marquez MF, Hernandez-Pacheco G, Hermosillo AG, Gomez JR, Cardenas M,
Vargas-Alarcon G. The Arg389Gly beta1-adrenergic receptor gene polymorphism
and susceptibility to faint during head-up tilt test. Europace 2007;9:585–8.
31. Lelonek M, Pietrucha T, Stanczyk A, Goch JH. Vasovagal syncope patients and the
C825T GNB3 polymorphism. Anadolu Kardiyol Derg 2007;7:206 – 8.
32. Carrega L, Saadjian AY, Mercier L, Zouher I, Berge-Lefranc JL, Gerolami V et al.
Increased expression of adenosine A2A receptors in patients with spontaneous
and head-up-tilt-induced syncope. Heart Rhythm 2007;4:870 –6.
33. Thijs RD, Kruit MC, van Buchem MA, Ferrari MD, Launer LJ, van Dijk JG. Syncope
in migraine: the population-based CAMERA study. Neurology 2006;66:1034 – 7.
34. Chen LY, Shen WK, Mahoney DW, Jacobsen SJ, Rodeheffer RJ. Prevalence of
syncope in a population aged more than 45 years. Am J Med 2006;119:1088 –7.
35. Ditto B, Adler PS, France C, France J. Family history of hypertension and vasovagal
symptoms during blood donation. J Behav Med 1995;18:331 – 40.
36. Romme JJ, van Dijk N, Boer KR, Dekker LR, Stam J, Reitsma JB et al. Influence of
age and gender on the occurrence and presentation of reflex syncope. Clin Auton
Res 2008;18:127 –33.
37. Toft E, Aaroe J, Jensen BT, Christiansen M, Fog L, Thomsen PEB et al. Long QT
syndrome patients may faint due to neurocardiogenic syncope. Europace2003;5:
367 –70.
L.R.A. Olde Nordkamp et al.
38. Dietz NM, Rivera JM, Eggener SE, Fix RT, Warner DO, Joyner MJ. Nitric oxide
contributes to the rise in forearm blood flow during mental stress in humans.
J Physiol 1994;480:361–8.
39. el Bedawi KM, Wahbha MA, Hainsworth R. Cardiac pacing does not improve
orthostatic tolerance in patients with vasovagal syncope. Clin Auton Res 1994;4:
233 –7.
40. Kaufmann H, Hainsworth R. Why do we faint? Muscle Nerve 2001;24:981 –3.
41. Vanderheyden M, Goethals M, Nellens P, Andries E, Brugada P. Different humoral
responses during head-up tilt testing among patients with neurocardiogenic
syncope. Am Heart J 1998;135:67–73.
42. Brewster L, van Dijk N, Mairuhu G, van Montfrans GA, Wieling W. Creatine
kinase and the cumulative incidence of fainting in a random population sample.
J Hypertens 2006;24:S304.
43. Jardine DL, Melton IC, Crozier IG, Bennett SI, Donald RA, Ikram H. Neurohormonal response to head-up tilt and its role in vasovagal syncope. Am J Cardiol
1997;79:1302 –6.
44. Douglas SA, Ohlstein EH. Human urotensin-II, the most potent mammalian
vasoconstrictor identified to date, as a therapeutic target for the management
of cardiovascular disease. Trends Cardiovasc Med 2000;10:229 –37.
45. Leiper J, Nandi M, Torondel B, Murray-Rust J, Malaki M, O’Hara B et al. Disruption
of methylarginine metabolism impairs vascular homeostasis. Nat Med 2007;13:
198 –203.
46. Karemaker JM, Wesseling KH. Variability in cardiovascular control: the baroreflex
reconsidered. Cardiovasc Eng 2008;8:23 –9.
47. Mehta AV, Chidambaram B, Garrett A. Familial symptomatic sinus bradycardia:
autosomal dominant inheritance. Pediatr Cardiol 1995;16:231–4.
48. Cooke WH, Ludwig DA, Hogg PS, Eckberg DL, Convertino VA. Does the
menstrual cycle influence the sensitivity of vagally mediated baroreflexes? Clin
Sci (Lond) 2002;102:639 –44.
49. Bosser G, Caillet G, Gauchard G, Marcon F, Perrin P. Relation between motion
sickness susceptibility and vasovagal syncope susceptibility. Brain Res Bull 2006;
68:217 – 26.
50. Robertson D, Biaggioni I, Ertl AC, Robertson RM, Diedrich A, Blakely RD et al.
Orthostatic intolerance: emerging genetic and environmental etiologies. J Gravit
Physiol 1999;6:51 –4.
51. Robertson D, Flattem N, Tellioglu T, Carson R, Garland E, Shannon JR et al.
Familial orthostatic tachycardia due to norepinephrine transporter deficiency.
Ann N Y Acad Sci 2001;940:527 –43.
52. Garland EM, Black BK, Harris PA, Robertson D. Dopamine-beta-hydroxylase in
postural tachycardia syndrome. Am J Physiol Heart Circ Physiol 2007;293:H684 –90.
53. Garland EM, Raj SR, Black BK, Harris PA, Robertson D. The hemodynamic and
neurohumoral phenotype of postural tachycardia syndrome. Neurology 2007;69:
790 –8.
54. Vincent S, Robertson D. The broader view: catecholamine abnormalities. Clin
Auton Res 2002;12:I44 –9.
55. Lifton RP, Gharavi AG, Geller DS. Molecular mechanisms of human hypertension.
Cell 2001;104:545–56.
56. Sprung J, Distel D, Grass J, Bloomfield EL, Lavery IC. Cardiovascular collapse
during anesthesia in a patient with preoperatively discontinued chronic MAO
inhibitor therapy. J Clin Anesth 1996;8:662–5.
57. Morris JA, Blount RL, Brown RT, Campbell RM. Association of parental psychological and behavioral factors and children’s syncope. J Consult Clin Psychol 2001;69:
851 –7.
58. Blount RL, Morris JA, Cheng PS, Campbell RM, Brown RT. Parent and child
psychological factors in pediatric syncope and other somatic symptoms.
J Consult Clin Psychol 2004;72:597 – 604.
59. Moss PD, McEvedy CP. An epidemic of overbreathing among schoolgirls. Br Med J
1966;2:1295 –300.
60. Bouter LM, van Dongen MCJM, Zielhuis GA, Kiemeney LALM. Genetical epidemiology. In Bouter LM, Dongen MCJMv, Zielhuis GA (eds). Epidemiological Research:
Set-up and Interpretation. Houten: Bohn Stafleu Van Loghum; 2005. p201 – 20.