Advance in the understanding of vasovagal syncope in children and adolescents

Hong-Xia Li ·Lu Gao ·Yue Yuan

Abstract Background Vasovagal syncope (VVS) accounts for 60—80% of cases of neurally mediated syncope.VVS results from acute orthostatic intolerance and recurrent syncopal attacks,which can seriously affect an individual’s quality of life.In addition,some children even experience trauma during attacks.Therefore,it is particularly important to clarify the pathogenesis of VVS.The aim of our study is to reveal the latest research progress of VVS.Data sources Literature that involved the pathogenesis of VVS were selected from Cochrane Library (1990—2019),EMBASE(1991—2019) and PubMed (1968—2019) databases.Results Hypovolemia,autonomic dysfunction,vasomotor dysfunction,baroreceptor reflex abnormalities,endothelial dysfunction,serotonin surges,and gut microbiota were involved in the underlying mechanism of VVS.Conclusions VVS is not always a benign prognosis.Various aspects were involved in its pathogenesis.Bezold—Jarish reflex,dysfunction of the autonomic nervous system,genetic factors and so on played important roles in VVS;however,the mechanism remains unclear.

Keywords Autonomic nervous system·Bezold—Jarish reflex·Children·Genetic pathogenesis · Vasovagal syncope

Introduction

Vasovagal syncope (VVS) is characterized by peripheral vasodilation stimulated by certain inducements,which lead to transient cerebral ischemia,presence of transient loss of consciousness and loss of body balance [1,2].VVS is the most common type of autonomic nerve-mediated syncope,accounting for more than 60—80% of syncope in children[2].Recent studies suggest that the prognosis of VVS is not always a benign condition [3].Kruit et al.discovered that frequent syncope and orthostatic intolerance increased the risk of white matter lesions,particularly in females [4].In the present article,we summarize the research progress on the pathogenesis of VVS in children.

The abnormal Bezold-Jarish reflex

When children are stimulated by standing for a long time,by emotional tension or by sultry environment,deposition of blood in the peripheral venous pool can occur,which contributes to insufficient blood returning and triggers Bezold—Jarish reflex.Subsequently,a sympathetic nerve impulse is increased while vagal nerve impulse is decreased to ensure the normal volume of returning blood and adequate cerebral blood supply.Children with VVS commonly had high levels of catecholamine,thus causing excessive contraction of the heart and an abnormal Bezold—Jarish reflex.Based on the above points,the baroreceptor of the posterior inferior wall of the left ventricle was activated,and the impulses were transferred to the vasomotor center through C fibers,which caused the decrease of sympathetic impulses and increase of vagal impulses,further resulting lower blood pressure and insufficient cerebral blood supply in VVS children with loss of consciousness or syncope [5].

Dysfunction of autonomic nervous system

The function of the autonomic nervous system can be evaluated by parameters of cardiac electrophysiology,such as heart rate variability (HRV),dispersion of Q—T,dispersion of P waves,ventricular late potential (VLP),and deceleration capacity (DC).

It was confirmed that compared with healthy children,root mean square of successive differences,adjacent NN intervals differing by more than 50 ms,and high frequency (HF) were significantly decreased in VVS children in the basal state,and low frequency (LF) was significantly elevated,which indicated that sympathetic impulses were enhanced and vagal impulses were weakened in VVS children [6].Evrengul et al.[7]revealed that the changes of LF,HF,and LF/HF were significantly higher in children with VVS than those in healthy children in the head-up tilt test (HUTT).However,LF/HF decreased significantly,HF increased significantly when syncope occurred,which suggested that sympathetic impulses reduced and vagus nerve impulses increased.Ak?aboy et al.[8]believed that there was no significant difference in baseline HRV between asymptomatic VVS children and healthy children.

K?se et al.[9]showed that the Pmaxand Pdin the supine position of the HUTT were significantly higher in VVS children than those in healthy children,which could reflect the autonomic dysfunction safely and non-invasively.A study of VLP found that VLP in VVS children was different from healthy children,which also suggested that VVS children had a risk of malignant arrhythmia and should be paid attention.A recent investigation showed that syncopal period caused significant increase of DC in positive groups of VVS children in HUTT [10].

The change of parameters,such as HRV,dispersion of Q—T,dispersion of P waves,VLP,and DC might indicate the dysfunction of the autonomic nervous system,which provided a new therapy target of VVS.However,the above parameters may be influenced by many factors.

Neuro-humoral factors

In VVS children,the level of catecholamine in the blood increased in the supine position,especially the adrenaline content [11— 13].Chosy et al.also found that the level of catecholamine in urine was higher in patients with syncope,and Chan et al.found that the average resistance of the circulation was mainly controlled by the sympathetic nervous system [12,13].The concentration of noradrenaline and adrenaline in the serum of VVS patients has also been reported to be slightly higher than those in the serum of people without VVS in the supine position.It has also been shown that serum adrenaline began to increase before syncope occurred,continued to rise during an attack,and increased by up to five times the original levels [14— 16].It is likely that levels of catecholamines vary in different hemodynamic types of diseases [16].

The above findings provided treatment direction for VVS.However,the content of catecholamines was affected by sports,emotion and posture.

The increase of flow-mediated vasodilation

The increase of flow-mediated vasodilation (FMD) in VVS children was confirmed in many studies [2,17].Liao et al.discovered that hydrogen sulfide (H2S) and nitric oxide(NO) played important roles in the increase of FMD,which was involved in the pathogenesis of VVS [17,18].Because of sympathetic over-excitation in VVS children,plasma catecholamine levels were higher than those in healthy children.NO synthase could be activated by β-2 receptors,accordingly increasing NO release from vascular endothelium and leading to excessive vasodilation.It is shown that the levels of asymmetric dimethylarginine,which is the inhibitor of NO,significantly decreased after the HUTT in patients with VVS in the latest study [18].Therefore,FMD was significantly higher than that in the control group and Bezold—Jarish reflection was inspired,which was responsible for the occurrence of syncope.

Further studies by Yang et al.[2]found that plasma H2S levels were significantly higher in VVS children than those in healthy children.In addition,plasma H2S levels were positively correlated with FMD.We also discovered that FMD and plasma H2S levels were significantly higher in children with VVS-cardioinhibitory (VVS-CI) than in children with VVS-mixed inhibitory (VVS-MI),which was speculated that erythrocyte-derived H2S increased,and then FMD value increased,resulting in the decrease of blood pressure.

In addition,Gallegos et al.[18]showed that blood soluble tumor necrosis factor receptor1 (sTNFR1) might also be involved in the pathogenesis of VVS in adolescent VVS patients.The probable mechanism was as follows:sTNFR1 suddenly decreased under the premature action of standing and body position changes.which weakened the inhibition of TNF down-threshold signaling and thereby increased the secretion of prostaglandin E2 and NO,resulting in vasodilation and syncope.Previous studies have shown that many other factors,such as adenosine and endothelin-1,might be involved in the FMD mechanism in VVS children.These studies showed that a vasoconstrictor might be an effective therapy for VVS.

The increase of plasma C-type natruretic peptide and decrease of plasma neuropeptide Y

We also discovered that the plasma of C-type natruretic peptide (CNP) was higher than that in healthy children [19].CNP is a small molecule protein that was isolated by Sudoh et al.from the tissue of a porcine brain in 1990 [20].Related studies indicated that CNP had a relaxing effect on vessels[21,22]by which CNP participated in the pathogenesis of VVS.

Previous studies documented that the supine plasma neuropeptide Y (NPY) levels were significantly reduced in children with VVS.NPY might play a role in the pathogenesis of VVS by increasing the total peripheral vascular resistance(TPVR) and by decreasing CO during orthostatic regulation[23].NPY,another biological active peptide,plays a crucial role in the regulation of blood pressure (BP),as well as myocardial contractility,which are closely associated with the pathogenesis of VVS.In the peripheral nervous system,NPY participates in the regulation of autonomic nervous function by mediating vasoconstriction and by increasing peripheral vascular resistance [24].In research on rats,after injecting NPY into the lateral ventricle,a decrease in the peripheral sympathetic nervous activity and a reduced norepinephrine release were observed,which resulted in decreases in both HR and BP [25].

The decrease of serum iron and serum ferritin

Jin et al.found that VVS children had lower serum iron (SI)and serum ferritin (SF) [26].In the same year,Guven et al.also found that SF was decreased in children with VVS [27].Iron in the body might regulate the activity of catecholamine,5-hydroxytryptamine and NO in the blood by which iron had regulation of activity of monoamine oxidase and NO synthase,therefore,was associated with pathogenesis of VVS.These findings indicated that the supplement of iron might improve clinical manifestations of VVS.

The change of hemodynamic of VVS

Coupal et al.found that a significant decline in cardiac output in adults with VVS was related to a drop in blood pressure in the early stage of syncope.This decrease in cardiac output might be the main contributing factor to the onset of VVS in the majority of patients [28].Fu et al.revealed that adult female patients with VVS exhibited a decline in heart rate resulting from decreased cardiac output,whereas no obvious changes were noted in TPVR [29,30].Stewart et al.discovered that both TPVR and cardiac output decreased in young VVS patients [5].Verheyden et al.discovered that in nitroglycerin-induced HUTTs,cardiac output falls rapidly in adults with VVS,leading to hypotension and the subsequent occurrence of syncope [31].Shinohara et al.revealed that baroreflex sensitivity indices were lower in a HUTT positive group than in a HUTT negative group in isoproterenol-induced HUTT [32].However,the dynamic changes in TPVR and cardiac output that occur during the HUTT are controversial,and the change in baroreflex sensitivity in children with VVS remains unclear.The dynamic change of hemodynamic in VVS children was observed by our study,in which children with VVS demonstrated increases in TPVR but decreases in cardiac output during the transition from the supine position to the positive response during HUTT.This response might be involved in the pathogenesis of VVS [1].

When the cerebral blood perfusion pressure changes within a certain range,the blood vessels of the brain could maintain a stable blood supply to the brain through a certain self-regulation mechanism.Previous studies showed that VVS children exhibited abnormal cerebral blood flow regulation when attacked by syncope.However,the dynamic change in cerebral blood flow needs to be further studied.

Genetic pathogenesis

Up to now,genetic pathogenesis of VVS has been less known.Previous studies have shown that VVS has a genetic predisposition.Current studies on the pathogenesis of VVS genetics focus on the autonomic nervous system associated with abnormal cardiovascular reflexes.There are many candidate genes [33],but few studies have focused on VVS of children.Some studies have found thatGPR174,a gene encoding GPR174 protein that forms a G protein-coupled receptor,andGNG2,a gene encoding the G protein gamma subunit,might be associated with VVS in children [34].Despite this,little is known about the role of gene mutation in the mechanism of VVS.Further studies are urgently needed.

Gut microbiota

Fecal samples from 20 VVS children and 20 matched controls were collected,and the microbiota was analyzed by 16S rRNA gene sequencing.Bai et al.discovered that ruminococcaceae was the predominant gut bacteria and was associated with the clinical symptoms and hemodynamics of VVS,confirming that gut microbiota might be involved in the development of VVS [35].

Conclusions

Many factors,such as abnormal Bezold—Jarish reflex,dysfunction of autonomic nervous system,and neuro-humoral factors,etc.explained the mechanism of VVS to some extent which also provided therapeutic options for VVS.However,the pathogenesis of VVS needs to be studied further.

Author contributionsLHX has finished the retrieval of literatures and wrote the first draft.GL revised the the first draft.YY analyzed the literatures and revised the first draft.All authors approved the final version of the manuscript.

FundingNone.

Compliance with ethical standards

Ethical approvalThis article does not contain any studies with human participants or animals performed by any of the authors.

Conflict of interestThe authors declare that we have no conflict of interest.