This study includes retrospective data analysis of 511 patients (64% female) referred to the Head Tilt Test (HUT) between 2015 and 2024, after suffering a vagal syncope.

The mean age of these patients was 30.8 years (range: 6 - 89 years).

We selected 188 cases (37%) in our study group whose syncopes were associated with pain (somatic, visceral, trauma, blood draws, vaccinations, etc.) or emotional stress.

We compared them with those individuals (control group) in whom vagal syncope is triggered by orthostatism after a period of standing (n: 323/63%) which is not the case in our patients.

More ominous causes, such as those related to arrhythmias and valvular abnormalities, such as ventricular tachycardia, atrioventricular (AV) block, or critical aortic stenosis, were excluded from our study.

Our patients are Chileans, of mixed Hispanic or Latin-European descent.

The exam is performed on an empty stomach, between 8 a.m. and 12 p.m., In a quiet, dimly lit room with a temperature between 20˚C and 22˚C. A neurologist, a cardiologist, and a medical technologist participate. Continuous electrocardiographic monitoring is performed by cardiology staff.

To rule out hypoglycemia, a blood glucose test is performed prior to the exam.

A record of heart rate (HR) and blood pressure (BP) and of symptoms reported by the patient is kept every 5 minutes. The reason for stopping the examination or any important incident is noted and recorded at any time. The sublingual spray nitroglycerin protocol (0.4 ug) is based on Del Rosso [5] .

Time line: Initial questioning (15 minutes)/Monitoring installation (digital cuff to measure BP and continuous electrocardiogram) (10 minutes)/Basal HUT (horizontal) for 10 minutes/Passive HUT (standing at 70˚) 45 minutes. Active HUT with 0.4 ug of sublingual spray of trinitrin (without laying the patient down) for 10 minutes/final recovery lying down (10 minutes) Total HUT: 55 minutes. Approximate total, time: 95 minutes.

Carotid massage is performed on all patients over 60 years of age. Previous discard of murmur or carotid stenosis or stroke in the last 6 months. Five minutes on each side (11).

Head-Up Tilt Table Test ends if a “positive HUT” is obtained: This is syncope (loss of consciousness) or presyncope (dizziness, nausea, paleness, etc., announcing that syncope is imminent). Associated with low blood pressure (Systolic BP < 70 mmHg) or low blood pressure plus bradycardia, or if intolerable patient discomfort occurs.

If there are no symptoms, it is terminated due to the end of the protocol.

The equipment consists of: Digital monitor (Ohmeda 2300 Finapres BP Monitor USA). Digital cuff placed on the index or middle finger to measure BP and HR continuously.

Electric tilting table (Magnetic Manumed USA) and electrocardiogram monitor (Quinton Q4500 USA). The patient is fastened to the table with two velcro straps (knees and chest).

Venous congestion with a score ranging from 1 to 5, was measured using a colorimetric method, with visual observation of color and venous congestion in the lower extremities and feet, and comparing these findings with standardized photographs for each range.

For the statistical comparison, data is analyzed by χ² test, anova and logistic regression, and depending on the sample size, a non-parametric test is used.

Our study was analyzed and approved by the institutional ethics committee of the Hospital Militar, and was carried out in accordance with the ethical standards of the Helsinki Declaration 1964. Patients and controls signed an informed consent before inclusion.

1) Vaccination or blood extraction n: 36, 2) Insurmountable fear (earthquake or arachnophobia) n: 6, 3) Academic stress n: 140, 4) Fall or strong blow n: 18, 5) Cut or bleeding n: 10, 6) Abdominal or menstrual pain n: 18.

In Table 2 , we show the types and number of events triggered by P/E.

*Some different triggering events can occur in the same patient. They are usually female. The most common combinations are: vaccination/blood draw + menstrual pain and vaccination/blood draw + academic stress.

Female patients represented 64% (n: 325) of the total cases sent to HUT (n: 511), compared to 36% (n: 186) in males. This difference was even greater in our patients with P/E-triggered syncope, female (74%) vs. male (26%) (n: 139 vs. 49) (p ≤ 0.05).

This is exactly the opposite in the male sex, where syncopes not triggered by P/E predominate (42% vs 26%) [6] (p ≤ 0.05).

Of our P/E patients with a severe level (>5) of joint hypermobility syndrome (JHS), 65% are women. Even more women constitute 68% of those who have severe (grade 4) or very severe (grade 5) of venous congestion (venous pooling) during prolonged standing, versus women whose syncope is not triggered by P/E (orthostatic syncope): 58% (p ≤ 0.05).

The average age of onset of syncope in our patients was 20 years old, compared to non P/E patients, where this age was 29 years. In females, the earlier age of onset was even more noticeable in P/E cases: 19 years (female) versus 27 years (male) (p ≤ 0.05).

In our non P/E patients, the predominance of females was also observed, with a younger age of onset of syncope: 25 years (female) versus 33 years (male) (p ≤ 0.05).

Cases with a hereditary history of P/E syncope have an average onset at 16 years of age, compared to 31 years of age in the hereditary group without P/E (p ≤ 0.05). Inheritance in our cases with P/E syncope occurs at earlier ages, especially in women (χ: 12 years old).

A history of vagal syncope in first-degree relatives (mother, father, children, siblings) is very common. All patients were given a questionnaire asking if they knew of any other family members affected by vagal syncope or fainting.

In our P/E patients (n = 188), we found a history of syncope in these first-degree relatives (83/188 = 44% frequency). Inheritance occurs mainly through the maternal branch (83%), more often than through both branches (maternal and paternal) (14%), and rarely only through the paternal line (3%) (p ≤ 0.05).

On the contrary, of the patients with orthostatic syncope (not triggered by P/E): 323 cases, only 13% (n: 42) (p < 0.05) had a history of syncope in first-degree relatives. A main predominance of female inheritance was also observed in these patients.

See data on inheritance patterns in first degree relatives in Figure 2 .

We found data on the parents (29 mothers, 9 fathers) of our P/E patients who recalled the presence of emotionally/pain triggered fainting spells in their own parents, siblings, aunts, or uncles (second-degree relatives): 20%.

In cases of orthostatic syncope (non P/E), we found only 9 mothers and 3 fathers who recalled the presence of P/E-triggered syncope in their ancestors (4%). (p ≤ 0.05).

See these data in Figure 3 .

We thus postulate a certain hereditary continuity of syncope triggered by P/E. Especially through the maternal line. Even in our non P/E cases (orthostatic syncope), maternal branch is the main line of inheritance of vasovagal syncope.

Even maternal inheritance is closely linked to the presence of joint hypermobility syndrome in our female patients (n: 56 = 61%).

Of the 511 patients studied, 235 (46%) had joint hypermobility (score 5 or ≥ on the “Beighton Scale”) [7] .

We notice a hereditary tendency of joint hypermobility syndrome in our patients P/E = 48% versus in non P/E cases: 35% (p ≤ 0.05).

We observed a relationship between the accumulation of “venous pool” in lower extremities and syncope during the passive phase (45 minutes) of HUT. Venous congestion was measured by visual observation of the color and congestion in lower extremities and feet with a score ranging from 1 to 5. And compared to a standard set of photographs for each range.

1 = nothing (little or no change in color of feet), 2 = mild (pinkish feet), 3 = moderate (reddish feet), 4 = severe (dark reddish feet) and 5 = very severe (acrocyanosis and purple feet). This system has been already explained in our previous publication [8] . In Table 3 , we show the colorimetric scale with our classification for the different degrees of venous pooling.

Of the patients with P/E syncope, 74% presented moderate, severe, or very severe (grades 3, 4 or 5) venous pooling during the passive HUT. Of these, 82% had a positive HUT for vasovagal dysautonomia. Of the patients with non P/E syncope, 65% presented equivalent grades of venous pooling and, of these, only 68% had a positive HUT for vagal syncope (p ≤ 0.05).

The increase in venous congestion during prolonged standing in our patients is related to:

1) Female sex: Venous pooling is much higher in women (55%) than in men (33%) (p ≤ 0.05). In female patients with orthostatic episodic syncope, it was 47%.

2) Joint hypermobility: Venous congestion during standing is higher in our patients with joint hypermobility (74%) versus non P/E cases (65%). (p ≤ 0.05).

3) Inheritance: We observed a higher frequency of hereditary history of P/E syncope in patients with greater venous congestion during prolonged standing, 78% of patients with severe venous congestion and hereditary history, versus non P/E cases: 62% (p ≤ 0.05).

This may be greatly influenced by the high proportion of people with joint hypermobility and Ehlers-Danlos syndrome type 3 in Chile [9] .

There is a positive association between anxiety and panic and a positive HUT [2] [10] [11] , and between recurrent vagal syncope and emotional stress [11] .

Intense fear can motivate us to act (fight or run away) or, conversely, it can paralyze us and prevent us from acting, triggering fainting, postural dizziness, or even urinating or defecating (in extremely frightened people) [12] [13] .

In nature, it is seen in animals that “play dead,” such as the opossum, some snakes, and some birds, because this confers a survival advantage during periods of unavoidable threat [14] .

This applies to humans in what is known as the “Paleolithic threat hypothesis,” which postulates that, in fear-induced fainting, genomes associated with life-threatening situations, such as encountering “a stranger holding a sharp object,” are selected and inherited [15] .

Thus, there would be an enhanced heritable predisposition to abruptly increase vagal tone and collapse flaccidly, rather than attempting to flee or fight in response to fear or threat. Even a minor injury or the sight of blood may have evolved as a response associated with this fear circuit. Such a “paradoxical” hemodynamic predisposition will increase the chances of survival for some individuals [15] [16] .

There are cases of soldiers in battle or about to be shot who survive after fainting [16] . Or young women who, when they faint, are kidnapped alive to be enslaved, and the fainting prevents them from being killed [15] [16] .

Therefore, we believe the Paleolithic threat hypothesis fits perfectly with some of our findings, such as the strong female predominance (74% vs 26% in male) and strong maternal inheritance in our patients (83% for us).

Thus, we propose that the maintenance of this mainly maternally inherited reflex in evolution supports the survival of the female sex, which is essential for the survival of the human species.

The Paleothreat hypothesis is consistent with our observation of a pattern of fear-induced fainting at a young age, primarily in women, which could explain what is observed in disasters such as earthquakes, terrorism against civilians, or traumatic events, where epidemics of fear-induced fainting or imitation of others occur in very young women [15] [17] - [21] .

Ultrasound scans show how stress induces left ventricular sympathetic hypercontractility, but the reduced venous return that occurs in the HUT activates an inhibitory vagal reflex in some individuals, slowing the heart rate. This would constitute a beneficial cessation of the heart’s pumping function, since it would reduce myocardial oxygen consumption, allowing better diastolic filling and coronary perfusion [22] [23] .

Functional MRI studies have investigated arachnophobia versus injection or blood draw phobia. The degree of anxiety and disgust is greatly enhanced by activation in some regions common to both groups, such as the thalamus, cerebellum, and occipitotemporal regions [24] - [26] .

The group with a phobia of injection or blood draw is characterized by greater activation in the thalamus and visual/attention areas (occipitotemporoparietal cortex). Patients with arachnophobia show greater activation in the dorsal anterior cingulate cortex and anterior insula compared to injection-phobic patients and healthy controls [27] - [29] .

Sex hormones play an important role (with an explosion during adolescence) in shaping neuronal structure and connections in the thalamus and visual/attention areas (occipitotemporoparietal cortex), dorsal anterior cingulate cortex, amygdala, and anterior insula [30] - [32] and the high presence of progesterone receptors on noradrenergic neurons in the nucleus of the solitary tract (vagal nerve), in the region whose connections project to the supraoptic nucleus of the hypothalamus [33] . And from the hypothalamus, there are connections that regulate the stress responses of the sympathetic and parasympathetic systems in the brainstem and spinal cord [34] [35] .

This may explain some rapid and automatic emotional reactions that override rational thought and occur in situations of great fear or risk. This is known as “amygdala hijacking,” where emotional reactions become disproportionate to the actual threat [36] , and these are more frequent and intense in women [37] [38] .

The genetic tendency to suffer from vasovagal syncope is clear [39] - [41] . Family history is described in about 20% of these patients [42] [43] . The presence of vasovagal syncope shows much higher concordance in monozygotic twins than in dizygotic twins [44] . Klein [44] believes that the tendency to experience vasovagal syncope is inherited in an autosomal dominant manner, via genes on chromosome 15. This would bring us closer to understanding the biological basis of syncope and maybe allow for future gene therapies [44] .

Multiple genetic variants associated with hypotension and/or vasovagal syncope have been described. For example, variants exist in the chromosomes that regulate blood pressure control mechanisms [45] [46] , in neurotransmitters related to the synthesis of norepinephrine [47] , in the absorption of salt in the renal tubule, as seen in the hereditary salt wasting of Gitelman syndrome [48] , or in alleles related to serotonin signaling [49] [50] , some of them associated with a decrease in syncope in men but an increase in women or vice versa [49] .

Studies support our observation about the heritability of vagal syncope in first-degree relatives [43] [49] - [53] , especially through the maternal line [41] [49] . It can also be inherited from the paternal side, but with a significantly lower frequency [49] .

Hypermobile patients experience significant venous congestion in their lower extremities when standing. This leads to impaired venous return, creating conditions for syncope due to systemic hypotension and cerebral circulatory deficit [54] . Skin biopsies show that the connective tissue in hypermobile individuals has a much higher proportion of type III collagen, which is more distensible. Their veins are much more congested when standing [9] [54] [55] . Furthermore, the hereditary tendency to ligament hyperlaxity is recognized as a risk factor for being a carrier of vagal syncope. This fact is known in the literature [9] [54] - [58] .