VVS

Introduction

Vasovagal syncope (VVS) represents the clinical expression of an autonomic neural reflex, the vasovagal reflex, that is present not only in humans but also in the other mammals and very likely in all the vertebrates.

VVS can be typical or nontypical. Typical VVS is diagnosed when LOC is precipitated by triggers such as strong emotion/fear or prolonged standing and is associated to autonomic prodromes (pallor, sweating, nausea, and abdominal discomfort). In about 80% of subjects with emotional VVS, LOC can be induced even during orthostatic stress (tilt testing).

Nontypical VVS includes episodes of LOC without any evident trigger and without (or only minimal) autonomic prodromes. Typical VVS generally starts at young age, and the natural history is extremely variable; some subjects experience only a single or a few episodes during their lives, whereas others have frequent episodes.

In the vast majority of subjects, typical VVS is not associated to cardiovascular, neurological, or other diseases, and therefore constitutes an isolated manifestation. VVS is benign and very frequent in the general population. The mechanism of the hypotension/bradycardia reflex responsible for VVS is not completely understood.

Very little is known about the afferent part of the vasovagal reflex (i.e., the step from trigger to autonomic control and central processing), whereas the efferent part of the reflex has been elucidated: hypotension appears to be secondary to transient inhibition of the sympathetic system and bradycardia to a transient increase in vagal tone together with cardiac sympathetic inhibition; this autonomic pattern is generally preceded by an increase in sympathetic activity. In humans hypotension and/or bradycardia are responsible for LOC through a global cerebral hypoperfusion.

Typical Vasovagal Syncope Is not a Disease

VVS is often regarded as a disease. That is probably true for VVS starting in old age, which is generally nontypical (without trigger and autonomic prodromes) and frequently associated not only to cardiovascular or neurological diseases, but also to other autonomic disturbances, mainly carotid sinus hypersensitivity. In other words, VVS in elderly seems to be related to the emergence of a pathological process involving the autonomic nervous system, not yet defined in nosology or, more in general, to aging processes. However, the efferent pathways leading to hypotension and bradycardia appear to be the same as in subjects with typical VVS.

Clinical psychologists believe that typical VVS is not a disease but an evolutionary selected trait. Three major lines of evidence support this view. First, the incidence of spontaneous VVS is exceedingly high. It has been reported that about 40% of young Dutch students with mean age of 21 years experienced spontaneous VVS, indicating that VVS is very common.

Second, the neural pathways involved in the vasovagal response, though not completely elucidated, are probably present in all (or almost all) healthy humans. Indeed, during diagnostic head-up tilt testing at 60–70^o, which induces thoracic hypovolemia through a venous pooling in the inferior part of the body, 10–15% of adult subjects without a history of fainting experience syncope (false positives).

Using stronger stressors, such as a tilting angle of 80^o in conjunction with low-dose isoproterenol, the percentage of subjects without history of fainting experiencing VVS increases to 40–45%. Among children, the percentage of asymptomatic subjects developing vasovagal reactions during tilt testing is also very high, approaching 40% even when a mild stressor is applied. Also astronauts, who are heavily selected on the basis of their great resistance to gravitational changes and cannot be regarded as sick individuals, have a 20% chance to experience presyncope or bradycardic syncope during upright posture on the day of landing, after a short-duration space flight. In some studies, subtle alterations have been reported in subjects with VVS during orthostatic stress: impaired venoconstriction, blunted increase in total peripheral resistance, higher increase in heart rate (HR), and enhanced sympathetic activity.

Impaired baroreflex sensitivity and reduced blood volume have also been described. However, other studies have failed to confirm these subtle alterations, and their presence is currently uncertain in subjects with VVS. A multiplicity of mechanisms may contribute to these discordant findings. 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.

All together, these data suggest that about 40% of young individuals experience spontaneous VVS, and a large fraction of the others experience VVS under orthostatic stress. Considering that orthostatic stress is not the only stressor known to evoke VVS, it seams reasonable to assume that the vasovagal reflex is predisposed in almost all individuals. Third, subjects with typical VVS are generally normotensive and do not have increased vagal tone during daily life. All these aspects of VVS are definitely not typical for a disease.

Since typical VVS is not a disease, but rather a manifestation of a non-pathological trait, we investigated the possible factors that can explain its origin and evolution. To this end, we conducted an extensive bibliographic research in order to analyze published theories dealing with the evolution of VVS and to investigate the vasovagal reactions in animals, including humans.

Evolution of Vasovagal Syncope

Two major theories have been put forward to explain the origin of VVS, here referred to as the Human Violent Conflict(s) and the Clot Production (Clotting) hypotheses.

According to the Conflict hypothesis, the VVS evolved during the Paleolithic era only in the human lineage. In situations of intergroup attacks and killing, LOC triggered by fear-circuitry activation might have conferred a survival advantage to noncombatants, particularly children and women, when threats were inescapable.

The second theory, the Clotting hypothesis, suggests that the vasovagal reflex is a defense mechanism against hemorrhage in mammals. During bleeding traumas, the reduction of BP in the context of the vasovagal reflex would give to the coagulation system a higher chance to produce a clot, thus arresting the loss of blood.

In addition to Conflict and Clotting theories, some authors have briefly mentioned two other hypotheses for the evolution of VVS. One of these hypotheses suggests that VVS is the human homolog of alarm bradycardia in animals, which is a decrease in HR documented in several species during fear-induced tonic immobility. In keeping with this hypothesis, the origin of VVS is therefore related to a selective advantage initially used by some ancestral groups when tonic immobility increased the survival during the interaction with predators.

Finally, the heart defense hypothesis proposes that VVS evolved as an advantageous mechanism to reduce myocardial oxygen consumption when cardiac strain is excessive. Both alarm bradycardia and heart defense hypotheses imply that VVS is just a manifestation in humans of a general response present in several other vertebrates. Vasovagal syncope and similar responses in other vertebrates should therefore share the same, or very similar, physiological mechanisms.

Vasovagal Reflex in Animals

When investigating the literature dealing with the vasovagal reflex in animals, including humans, researchers found two processes, which are relevant for the investigation of VVS evolution: alarm bradycardia during tonic immobility in animals and vasovagal reflex during hemorrhagic shock both in animals and humans. We found reports of vasovagal reflex only in vertebrates and not in invertebrates.

Before delving into these two processes, we briefly mention an additional mechanism, the “attentional” response, which has been related, sometimes, to vasovagal reflex in humans and animals.

Attentional Response

In humans, the general response to emotion or fear usually involves an increase in HR and BP. A sudden loud noise consistently evokes an acceleration in HR, whereas low-intensity auditory stimuli, or visual stimuli such as unpleasant pictures, can induce a reduction in HR.

In a subsequent study, however, a slowing of HR was observed in several subjects, regardless of the type of picture shown (pleasant, unpleasant, or neutral). In all cases, the reduction in HR was very limited (2–3 beats/min). It has been suggested that HR decreases in response to stimuli which require particular attention and detailed visual inspection (“attentional” or “alerting” response).

Similar responses have been observed in animals. In rabbits, a small reduction in HR has also been observed after low-intensity acoustic stimuli, sometimes associated with a slight decrease in blood pressure (~4 mmHg). The relationship between the attentional response and the vasovagal reflex has not yet been clarified, though recent data suggest that the physiological mechanism of the attentional response involves “vagal” ad not “vasovagal activation”.

Recently, attentional response was investigated during visual stimuli in two groups of subjects, one with and the other without history of VVS; this response showed similar characteristics in the two groups of subjects. This suggests that the attentional response and the vasovagal reflex should involve different mechanisms.

Alarm Bradycardia in Animals

The most common animal response to fear or threat is active, the so-called fight-or-flight, response, which is characterized by increased physical activity and systolic BP, dilation of muscle vessels, and tachycardia. In contrast to this active response, many animals can show a passive response to fear/threat by remaining motionless, above all when attacked by predators from which there is no possibility of escape.

Figure X1. Young mouse during tonic immobility, after the sudden approach of a dog. The animal assumes a recumbent posture to achieve the lowest body profile, in order to simulate the death

A variety of names have been used to describe this phenomenon: tonic immobility, hypnosis, death-feint, fright-paralysis, and playing dead. The most used term is tonic immobility.

During tonic immobility, which is a reflex and involuntary response, the animal typically assumes a recumbent posture to achieve the lowest body profile (Figure X1). Muscles are hypertonic, but a certain degree of relaxation is possible. Breathing is reduced in rate and amplitude. The animal is alert, as shown by electroencephalographic recording, but in a state of catatonic-like reduced responsiveness which simulates the death.

Two aspects of tonic immobility are relevant for our investigaton: the physiological modifications occurring during this behavior (alarm bradycardia) and its selective advantage. These physiological aspects are relevant because the alarm bradycardia hypothesis for the evolution of VVS suggests that alarm bradycardia during immobility behavior in animals and VVS in man are homologous. The selective advantage of tonic immobility is obviously relevant to explain its evolution.

The prevalence in the various animal species of alarm bradycardia during tonic immobility is unknown; sometimes an acceleration of HR has been observed. Even the reproducibility of alarm bradycardia has not been investigated. Extensive evidence, however, suggests that transient episodes of this phenomenon, documented by using a telemetric system, are common in mammals as well as in lower vertebrates.

Similarities Between Orthostatic Vasovagal Syncope in Man and Vasovagal Reflex During Hemorrhagic Shock in Animals

In these two situations the trigger appears to be the same, that is, thoracic hypovolemia, which is responsible for the vasovagal reflex during prolonged standing or diagnostic tilt testing in humans and hemorrhagic shock in animals and humans.

The efferent pathway also appears to be the same: an increase in sympathetic tone followed by withdrawal of the sympathetic drive to the heart and vessels, as shown by the sudden decrease in BP and by micro-neurographic recordings, followed by an increase in vagal activity, as shown by the slowing of HR.

Since the vasovagal reflex during hemorrhagic shock has been observed in rats, rabbits, cats, dogs, and apes as well as in humans with the same physiological mechanism, this means that the orthostatic vasovagal reflex is predisposed in primates and other mammals.

Similarities Between Emotional Vasovagal Syncope in Man and Alarm Bradycardia in Animals

Bradycardia occurs in humans during emotional vasovagal VVS and in animals during fear/threat, both in the context of tonic immobility and in the absence of this behavior, as in carnivores. Neuroscientists believe there is a similarity in the physiological mechanism responsible for bradycardia in humans and animals, for the following reasons:

1. the same trigger evokes the same type of response (bradycardia);
2. both emotional VVS in humans and alarm bradycardia in animals are more frequent in the young individuals than in the older ones;
3. both emotional VVS in humans and alarm bradycardia in animals are generally preceded by acceleration of HR, as an expression of increased sympathetic activity.

Unfortunately, BP has not been measured during alarm bradycardia in the context of tonic immobility, possibly because of limited availability of continuous BP measurements. This is a weak point in the analysis and interpretation of the vasovagal reflex.

However, in the only study in which both HR and BP were measured during fear induced bradycardia, the slowing of HR was associated in some individuals with a sudden decrease in BP; these cardiovascular changes elicited by a trigger such as emotion/fear suggest that we are dealing with a vasovagal reflex.

The similarities of the triggers and of the efferent response in the various types of vasovagal reflex suggests a common evolutionary root. Accordingly, typical VVS would not have evolved in the modern human lineage, as suggested in the Conflict theory, but it should be regarded as an advantageous response which originated in the ancient past within some ancestral groups of vertebrates.

If the vasovagal reflex is predisposed in all the vertebrates, from fishes to mammals, why is LOC present in humans, but absent (or extremely rare) in animals? Recently van Dijk offered a possible explanation based on some anatomical or physiological traits evolved in the human lineage:

• the metabolic demand for the brain is lower in animals than in humans; for example, in man about 20% of cardiac output is destined for the brain, while in apes (gorilla, chimpanzee) the proportion of cardiac output that needs to be pumped upwards is only 4–7%. As a consequence, a cerebral hypoperfusio severe enough to elicit LOC rarely occurs in animals or it does not occur at all;

• human legs are relatively more robust than hind legs in other primates or other tall or long-necked mammals, and muscle pump appears less active in man; as a consequence, upon assuming the upright posture, gravity causes more venous pooling in the human legs and, consequently, more orthostatic difficulties. In other words, the orthostatic vasovagal reflex appears to be predisposed in primates and other mammals.

However, for the abovementioned reasons, and because of the quadruped or recumbent position, this reflex is less likely activated in animals. When activated, the reflex cannot induce cerebral hypoperfusion severe enough to elicit LOC. Probably, for the same reasons, spontaneous emotional VVS is absent (or very rare) in primates and other mammals.

In man, who recently assumed an erect posture and developed a large brain, the vasovagal reflex can more easily induce severe cerebral hypoperfusion and, consequently, LOC. On the other hand, emotional VVS in humans appears to be extremely rare in the supine position. It is likely that, in this position, the vasovagal reflex-induced cardiovascular changes are not sufficient to elicit severe cerebral hypoperfusion.

Another hypothesis has recently been postulated to explain the occurrence of LOC only in humans, “the brain self-preserving response” (Blanc JJ et al., Personal communication).

According to this hypothesis, when the large human brain senses a decrease in blood supply, the autonomic nervous system is activated by an unknown mechanism in order to drastically decrease BP and HR up to LOC, which in turn results in a fall. Because of the new clinostatic position, BP and HR rapidly increase and the subject recovers consciousness without any damage to the brain. In other words, “the brain self-preserving response” should have developed during the evolution of human beings to protect the large brain. However, the mechanism of this response remains to be elucidated.

Vasovagal Reflex as a “Defense Mechanism”

If the vasovagal reflex has persisted for millions of years along the vertebrates evolutionary history, we can reasonably assume that it has a function and it is not harmful. It could be neutral or beneficial, but some observations suggest that it could be beneficial. Since this phenotype is sporadically displayed, a possible role such as a defense mechanism appears likely.

The open question is “what is the advantage of the vasovagal reaction?” In other words, which hypothesis best explains its evolution?

Did the vasovagal reflex evolve as an advantageous response to inescapable predators or to stressful and possibly dangerous heart conditions?

Vasovagal reflex as a possible defense mechanism for the heart

Under the first hypothesis, emotional VVS might be an evolutionary relict or correlate of a prey-related behavior. Alarm bradycardia is not a constant response during tonic immobility. However, when it occurs associated with the reduction of respiratory rate, it may help to better simulate death by lessening the movements and/or body sounds that a predator can detect.

On the other hand, under the heart defense hypothesis, the transient inhibition of the sympathetic system, together with the activation of the vagal system and consequent slowing of HR, may:

1. constitute a beneficial break of cardiac pump (thereby reducing myocardial 0₂ consumption),
2. permit better diastolic filling and coronary perfusion, and probably
3. ameliorate the pumping efficiency of the heart even if BP decreases (see Figure X2).

Thus, both the alarm bradycardia and heart defense hypotheses seem to imply a selective advantage which could explain the evolution of the vasovagal reflex. Presently, both advantages are possibly shared by several species. Only the heart defense hypothesis, however, naturally emerges as a unifying theory able to explain the occurrence of the vasovagal reflex and its associated selective advantage during both emotional and orthostatic stress. The hypothesis that alarm bradycardia during tonic immobility behavior improves survival is fascinating, but it does not directly explain the vasovagal reflex during orthostatic stress.

In conclusion, our extensive analysis of the literature suggests that typical VVS in humans has the same origin as the fear and threat bradycardia observed in all classes of vertebrates and the vasovagal reflex during hemorrhagic shock (thoracic hypovolemia) observed in humans and other mammals.

LOC due to the vasovagal reflex characterizes only humans and might be explained to be due to the erect posture and the large brain that evolved in our species. We also argue that VVS appears to be a defense mechanism evolved to protect the heart during stressful and possibly dangerous conditions. To this regard, it should be underlined that during the vasovagal reflex the transient withdrawal of the sympathetic system is generally preceded by increase in sympathetic activity.

The apparent paradox of high adrenaline level followed by transient sympathetic inhibition seems to be characteristic of the vasovagal reflex both in humans and animals. That is, the sympathetic system, activated up to a certain level, likely different from individual to individual, inhibits itself. This unique mechanism appears to be highly suggestive for a defense mechanism because high sympathetic activity could be dangerous.

As for other defense mechanisms, that is, antibody production, we should not forget that the vassovagal reflex is a potential source of negative effects in man, mainly due to the occurrence of LOC. In fact, fainting, which often occurs during upright posture, may lead to traumas. In some subjects, VVS may be frequent and responsible for psychological disorders. High recurrence rate of syncopal episodes and/or asystolic pauses, probably due to increased susceptibility, should be regarded as a harmful excess of the defense response. To date, the gene(s) responsible for the vasovagal reflex, and a possible genetic polymorphism responsible for enhanced susceptibility, have not been discovered.

Our analysis suggests that the bradycardia/hypotension reflex occurs in animals under triggers such as fear/threat or orthostatic stress (thoracic hypovolemia). Other triggers did not emerge, even if it is not possible to exclude other triggers under some pathological situations. Therefore, only the emotional or orthostatic vasovagal reflex, which occurs under high sympathetic activity, appears to be a physiological reflex; that should be relevant for the classification and perspective of reflex syncope in man.