SYNCOPE
Is vasovagal syncope a disease?
1 Division of Cardiology and Arrhythmologic Center, Ospedale Civile, Via Vicini 2, 44042 Cento (FE), Italy; 2 Department of Cardiology and Arrhythmologic Center, Ospedali del Tigullio, Lavagna, Italy; 3 Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Italy
Manuscript submitted 4 May 2006. Accepted after revision 16 November 2006.
* Corresponding author. Tel: +051 6838111; fax: +051 6838471. E-mail address: p.alboni{at}ausl.fe.it
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Abstract |
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 Top Abstract IntroductionIsolated VVSVasovagal diseaseConclusionReferences |
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Vavovagal syncope (VVS) is not generally associated with cardiovascular, neurological or other diseases, and, therefore, represents an isolated manifestation. Isolated VVS cannot be regarded as a disease for several reasons: spontaneous syncope occurs in about half of individuals during their lives, and the unidentified neural pathways involved in the vasovagal response are probably present in all healthy humans, with individual differences in susceptibility; VVS is induced during tilt testing in several subjects with no history of syncope; during haemorrhagic shock, the vasovagal reaction can be observed in subjects with no history of syncope; about 20% of astronauts, who are selected on the basis of their great resistance to orthostatic stress, experience syncope or presyncope on landing after a short-duration space flight; to date, no genetic basis of VVS has been demonstrated; subjects with VVS are generally normotensive and, importantly, have normal blood pressure regulation apart from the episodes of syncope; hormonal disorders or a generalized state of autonomic involvement, although frequently investigated, have never been clearly demonstrated. Isolated VVS should be distinguished from those forms that start in old age and which are often associated with cardiovascular or neurological disorders, and other dysautonomic disturbances such as carotid sinus hypersensitivity, post-prandial hypotension, and symptoms of autonomic dysfunction. In these subjects, VVS appears as an expression of a pathological process, i.e. a disease, mainly related to a generalized involvement of the autonomic nervous system, which is not yet well-defined from a nosological point of view.
Key Words: Vasovagal syncope, Syncope, Tilt test
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Introduction |
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Classical vasovagal syncope (VVS) is mediated by emotional or orthostatic stress and can be diagnosed by history taking.1
It is diagnosed when precipitating events such as fear, severe pain, emotional distress, instrumentation, or prolonged standing are associated with typical prodromal symptoms.1,2 Classical VVS generally starts at a young age, the most commmon age at which it first presents is 13 years,3 and the natural history is extremely variable; some subjects experience only a single episode during their lives, while others have frequent episodes. In the vast majority of subjects, VVS is not associated with cardiovascular, neurological or other diseases, and, therefore, constitutes an isolated manifestation (‘isolated VVS’). Vasovagal syncope is benign and very common; in fact, it was reported in 39% of young medical students (median age 21 years),4 and it is, therefore, more likely that up to 50% of all individuals experience loss of consciousness at some time during their lives. Most of these have only one or few episodes.2,4 Most subjects do not seek medical assistance.1 The pathophysiology of the hypotension/bradycardia reflex responsible for VVS is not completely understood. However, much evidence suggests that hypotension is secondary to transient withdrawal of sympathetic tone and bradycardia is secondary to a transient increase in vagal discharge. |
Isolated VVS |
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We believe that isolated VVS is not a disease for two main reasons:
- Spontaneous syncope occurs in about half of the individuals in their lives, but the unidentified neural pathways involved in the vasovagal response are probably present in all healthy humans, with individual differences in susceptibility. This assertion is supported by some data reported in the literature.
- Head-up tilt testing (HUT) is used to assess individual susceptibility to VVS and the results of most studies suggest that this test discriminates fairly well between adult subjects with syncope and asymptomatic control subjects. However, 10–15% of adult subjects without a history of fainting experience syncope during HUT at 60–70° (false positives). On using a stronger stressor, such as a tilt angle of 80° in conjunction with low-dose isoprenaline, the percentage of asymptomatic adults experiencing vasovagal reaction increases to 40–45%.5,6 Among children, the percentage of asymptomatic subjects developing vasovagal reactions during HUT is also very high, approaching 40% even when a mild stressor is applied.7 It should also be considered that orthostatic stress is only one of the many stressors known to provoke syncope. For example, the addition of instrumentation with an intravenous line during HUT, in both young and elderly subjects with no history of fainting, markedly increases the incidence of vasovagal reaction.8,9 These results suggest that about 50% of all individuals experience spontaneous fainting and about 40% of the other half experience VVS only under intense orthostatic stress. The autonomic reflex, therefore, appears to be predisposed in about 70% of all individuals.
- Haemorrhagic shock can present a situation similar to VVS. The volume loss caused by haemorrhage results in hypotension and a fall in venous return, which can lead to inappropriate sympathetic-inhibition and a subsequent paradoxical response characterized by a further fall in blood pressure, associated with bradycardia. This vasovagal reaction, which is probably secondary to a strong trigger such as a severe reduction in venous return, can be observed in subjects with no history of syncope10 and, therefore, cannot be considered an expression of a pathological disorder.
- Astronauts are selected on the basis of their great resistance to orthostatic and gravitational changes. Despite this selection, however, about 20% experience presyncope, and some experience a frank bradycardiac syncope during upright posture on the day of landing after a short-duration space flight.11 This has been attributed to central control system remodelling, which is a transient dysfunction of central integration of baroreflex afferent input as, during weightlessness, the central nervous system receives no baroceptor input from upright posture.11
The abovementioned considerations suggest that about half of healthy individuals experience spontaneous syncopal episodes during their lives and that many of the others have a susceptibility to VVS that can be unmasked by intense stress. An autonomic reflex which is potentially triggered in the vast majority of individuals cannot be regarded as a pathological disorder.
In addition, it should also be considered that:- To date, a genetic basis of VVS has not been demonstrated, though cases of familial VVS have been reported. A case-control study by Camfield et al.12 showed that, among children with VVS, a significant proportion had a parent or a sibling with syncope, an association not seen in control subjects. Mathias et al.13 reported a familial tendency for VVS, which was confirmed by HUT. They observed a positive family history of VVS in 90% of their group under the age of 20 years. Two sets of monozygotic twins with recurrent syncope have also been reported.14 However, these data do not show that the effect of family history is due to genetic factors; indeed, it remains possible that it is due to sociocultural, psychological, or environmental factors.
- Some authors suggested that spontaneous VVS has not been clearly demonstrated in animals.15 Even if quadrupeds are, very likely, less susceptible to VVS, we believe that some data suggest the possibility of a vasovagal reflex in mammals. In experimental studies carried out in rats, severe reduction in venous return induced reflex bradycardia and hypotension.16 Moreover, in some vertebrates tonic immobility occurs as a fear response in order to simulate death for self-defence. Reports on haemodynamic responses in tonic immobility are scarce, but bradycardia and lowered blood pressure have been demonstrated in some animals, particularly the opossum and some kinds of rabbits.17,18 It is not clear whether the vasovagal reflex is voluntarily induced or not. However an autonomic reflex aimed at self-defence cannot be considered a pathological finding.
- To date, a genetic basis of VVS has not been demonstrated, though cases of familial VVS have been reported. A case-control study by Camfield et al.12
- Head-up tilt testing (HUT) is used to assess individual susceptibility to VVS and the results of most studies suggest that this test discriminates fairly well between adult subjects with syncope and asymptomatic control subjects. However, 10–15% of adult subjects without a history of fainting experience syncope during HUT at 60–70° (false positives). On using a stronger stressor, such as a tilt angle of 80° in conjunction with low-dose isoprenaline, the percentage of asymptomatic adults experiencing vasovagal reaction increases to 40–45%.5
- Typically, subjects with VVS have no evidence of underlying heart or neurological disease. These subjects are generally normotensive and, importantly, have normal blood pressure regulation outside the episodes of syncope. In some studies,19–21 with one exception,22 the behaviour of blood pressure during the first minutes of HUT, before the beginning of the vasovagal reaction, was similar in VVS subjects and in control subjects without a history of fainting. Contrary to the general belief, subjects with VVS do not have an increased vagal tone during everyday life.23 These data suggest that a generalized state of autonomic involvement is not present in these individuals. Admittedly, in some studies subtle alterations have been reported in subjects with VVS during orthostatic stress: impaired venoconstriction,20,24 lower increase in total peripheral resistance,24 higher increase in heart rate,25 and enhanced sympathetic activity26; impaired baroreflex sensitivity26 and reduced blood volume27 have also been described. However, other studies have failed to confirm these subtle alterations21,28–35 and their presence is currently uncertain in subjects with VVS. A multiplicity of mechanisms may contribute to these different observations. In any case, these subtle alterations cannot be regarded as pathological disorders; at worst they are an expression of susceptibility to VVS. Moreover, a cause-effect relationship cannot be established.
Some observations have suggested that the serotoninergic system is impaired in subjects with VVS. The withdrawal of sympathetic outflow leading to hypotension could be mediated by serotonin. Indeed, the administration of intracerebroventricular serotonin induces inhibition of sympathetic nerve activity and hypotension.36 Thus, a sudden surge in central serotonin levels may contribute to the mechanism of sympathetic withdrawal. Theodorakis et al.37 observed that, during HUT, subjects with a typical history of VVS had increased prolactin and cortisol responses after infusion of clomipramine (a serotonergic re-uptake inhibitor) compared with a control group with no history of fainting, and it has been concluded that central serotoninergic mechanisms are involved in the genesis of VVS, on the assumption that this higher hormonal responsiveness to clomipranine could be a consequence of central serotoninergic activation. In a recent study carried out in a larger population,21 the response to orthostatic stress in terms of cortisol and prolactin secretion was similar in subjects with VVS and in a control group with no history of fainting; the authors concluded that the serotoninergic system is not impaired in subjects with VVS. Support for this conclusion has recently been provided by Alboni et al.38 who assessed the serotoninergic system by determining plasma and platelet serotonin levels during HUT in subjects with VVS. They did not observe any significant change in blood levels of serotonin at the beginning of the prodrome, during loss of consciousness and on recovery of consciousness. The inability to document increased serotoninergic system activation may be related to the fact that only peripheral measurements were taken. However, there is evidence indicating a good correlation between central and peripheral serotoninergic activity.39 In a small controlled study40 oral paroxetine, a serotonin receptor antagonist, improved symptoms in subjects with VVS; in another,41 however, oral paxil, another serotonin receptor antagonist, did not prevent the vasovagal reaction during orthostatic stress. To date, an impairment of the serotoninergic system in subjects with VVS has not been clearly demonstrated.
It has been suggested that other hormonal factors such as adrenaline,42 arginine vasopressin,43 beta-endorphins,44 adenosine,45 and galanin46,47 may play a role in eliciting VVS. However, a pathophysiological role of these hormonal factors has not yet been demonstrated.
In conclusion, on the basis of all the above findings, we believe that isolated VVS is not a disease, but rather the clinical manifestation of an autonomic reflex predisposed in all (or almost all) individuals. Why certain subjects appear to be more susceptible than others to the development of paradoxical hypotension and bradycardia, and why the event occurs at one time and not at another, remains unknown. However, this increased susceptibility can lead to trauma, severe anxiety, or depression.
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Vasovagal disease |
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The considerations reported above refer to classical VVS. However, the classification of the causes of syncope used by the Task Force on syncope of the European Society of Cardiology includes some forms of non-classical vasovagal syncope that are diagnosed on the basis of minor clinical criteria, exclusion of other causes of syncope (absence of heart disease), and positive response to HUT.1
Examples of non-classical VVS include episodes without (or with minimal) triggering events or prodromal symptoms. It is known that clinical manifestations change significantly in older subjects and that medical history has a limited value in establishing the cause of syncope in older people.48 In the EGSYS 2 study,49 the age of onset of VVS in 190 subjects admitted urgently to hospital was 52 ± 23 years (unpublished data). This study involved a population-based sample of consecutive patients referred to emergency departments, a sample which was biased only by access criteria. Their age distribution showed that the age of onset is distributed throughout life, peaking at the age of 20 and after the age of 70 years (Figure 1). In subjects in whom VVS starts in old age, loss of consciousness cannot be regarded as an isolated manifestation, as it is frequently associated not only with cardiovascular or neurological diseases but also with other dysautonomic disturbances, such as carotid sinus hypersensitivity, post-prandial hypotension, progressive orthostatic hypotension, and symptoms of autonomic dysfunction (abnormal sweating, abnormal thermoregulation, etc.).50,51 Even though VVS starting in old age shares the same pathophysiological mechanism of hypotension—bradycardia with isolated VVS both during HUT and during documented spontaneous syncope,50,52 these findings prompt us to regard it as an expression of a pathological process mainly related to a generalized involvement of the autonomic nervous system or, more generally, to the ageing process. Therefore, VVS starting in old age should be considered a disease, or, at least, part of a more complex disease. The clinical features of isolated VVS and of vasovagal disease are summarized in Table 1. Although this subdivision engenders the risk of oversimplification since several intermediate forms are present, we believe it may be useful for practical purposes. Vasovagal syncope starting in old age sometimes progressively worsens over time, and major injuries are frequent,52 mainly when a prodrome is lacking. In this regard, a specific therapy guided by electrocardiographic examination at the time of syncope recurrence has proved effective in relieving recurrences.52 In contrast, no specific therapy is generally warranted in most subjects affected by isolated VVS.
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Conclusion |
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TopAbstractIntroductionIsolated VVSVasovagal diseaseConclusionReferences |
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In conclusion, we believe that isolated VVS is not a disease, whereas VVS starting in old age appears to be an expression of a disease that has not yet been clearly defined from the nosological point of view.
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References |
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