FoxEmma-NeurocardiogenicSyncope

Pathophysiology of neurocardiogenic syncope: integration of the autonomic nervous and cardiovascular systems

Emma Fox

2016SS Human Physiology Capstone Project

College of Medicine

University of Cincinnati

Pathophysiology of neurocardiogenic syncope

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Fox, Emma

Abstract

Pathophysiology of neurocardiogenic syncope: integration of the autonomic nervous and cardiovascular systems. Emma Fox. Human Physiology, College of Medicine, University of Cincinnati, 2016SS.

Neurocardiogenic syncope—also called vasovagal syncope (VVS), amongst other names—is one of the most common forms of syncope in the general population, yet neither the pathophysiology nor prognosis is well understood. It is characterized by a sudden drop in heart rate and blood pressure, often triggered by stressful stimuli, that cause fainting. One possible mechanism of VVS is thought to be miscommunication between complex junctions of the neurological and cardiovascular pathways. Other hypotheses include the inhibition of crucial areas in the brain stem by higher areas of the cortex and the paradoxical firing of cardiac mechanoreceptors and venous baroreceptors in response to decreased central blood volume. No matter the mechanism of action, VVS results in temporary loss of consciousness and inability to maintain orthostasis followed by spontaneous recovery, accompanied by other symptoms including vasodilation, hypotension, bradycardia, pallor, diaphoresis, and altered vision. This paper reviews the existing literature on VVS and addresses the aforementioned physiological mechanisms of the syncopal response, with particular focus on inappropriate baroreceptor sensitivity (BS), sympathetic withdrawal, and parasympathetic activation. Also discussed are common symptoms, pathophysiology, incidence and prognosis, and controversy in research for VVS.


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Fox, Emma

Introduction

Syncope or the “common faint” is a clinical diagnosis that affects roughly 3% of men and 3.5% of

women (20). First described in the 1873 post-mortem publications of surgeon John Hunter, it is generally

characterized as a sudden loss of consciousness and an inability to maintain orthostasis followed by

spontaneous recovery (22). It accounts for roughly 3% of emergency department visits and 6% of

hospitalizations nationally (9). Nearly 40% of the adult population—healthy or not—will experience at least one

syncopal episode over the course of their lifetime (9). Reoccurring orthostatic intolerance can be dangerous as

it may lead to injury or significant decrease in quality of life (5, 14). These numbers reflect all types of syncope,

yet the numbers for a specific type of syncope known as neurocardiogenic syncope or vasovagal syncope

(VVS), are much higher. VVS is the most common form of syncope in young adults and accounts for nearly

21% of all syncope patients, accompanied by a cumulative lifetime incidence of 35% (6, 9, 22).

Although VVS is the most common form of syncope, its pathophysiology is not well understood. Many

hypotheses for mechanisms of the vasovagal response exist: One possible mechanism is the inhibition of

crucial areas in the brain stem by higher areas of the cortex (19). Other hypotheses include miscommunication

between complex junctions of the neurological and cardiovascular pathways involving inappropriate

baroreceptor sensitivity (BS), sympathetic withdrawal measured by muscle sympathetic nerve activity (MSNA),

and parasympathetic activation (1, 11).

The primary objective of this review paper is to discuss symptoms, pathophysiology, diagnosis,

incidence and prognosis, and controversy in research of VVS as each area is expressed in existing literature.

Discussion

Symptoms

The average age for onset of VVS symptoms is 13 years (21). Prodromal symptoms include

hypotension, dizziness, blurred vision, and brief loss of consciousness ranging from 5-20 seconds as a result


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Fox, Emma of paradoxical vagally-mediated vasodilation and bradychardia (13, 23). Recovery time is short, but

affected individuals will often experience periods of fatigue or retrograde amnesia following the syncopal

episode (4). In recent studies of clinical VVS, autonomic prodromal symptoms such as pallor, diaphoresis, and

abdominal pain have been documented in the brief period of pre-syncope and affect nearly 90% of patients (3).

This phenotype of parasympathetic activation and sympathetic withdrawal can be triggered by fear, pain,

prolonged orthostasis, emotional distress, and exhaustive exercise in patients diagnosed with VVS, with

exhaustive exercise being a factor capable of triggering both VVS patients and healthy individuals (3, 7).

Pathophysiology

As previously stated, the exact mechanism of VVS is not yet clear. Since bradychardia is one of the

classic symptoms of VVS, control of heart rate (HR) with the use of pacemakers was one of the first treatment

methods (4). One randomized, double-blind, placebo-controlled trial, however, produced significant data

showing the ineffectiveness of cardiac pacing in syncope management, indicating that other mechanisms may

be at play in the syncopal response (18).

It is well documented that transition from the supine posture to orthostasis encourages venous pooling

in the lower extremities and a decreased venous return (24). This results in acute central hypovolaemia or

decreased blood volume—a gravity-mediated phenomena that will, in healthy patients, lead to a sustained

sympathetic response in the form of vasoconstriction, tachycardia, and increased cardiac output (16). While

the initial sympathetic activation is triggered by low-pressure baroreceptors in patients with VVS, the response

is not sustained and thus leads to the paradoxical sympathetic withdrawal (16).

The inability to maintain the sympathetic response is, ironically, due to the same low-pressure

baroreceptors from which the response originates in peripheral circulatory structures. BS decreases

significantly sometime between the pre-syncope and syncope stages for reasons yet to be understood, later

leading to the withdrawal of sympathetic output (15). Some studies point to underlying reflex dysfunction as the

source of withdrawal (10).


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Fox, Emma

Shortly after decreased venous return, ventricular myocardial contraction increases and simultaneously

activates ventricular C fibers and other cardiac mechanoreceptors to elicit a paradoxical response from the

vasomotor area of the brainstem (11, 16, 24). This inappropriate activation of C fibers sends afferent signals to

the medulla oblongata, mimicking those seen in times of increased arterial pressure (24). The resulting

sympathetic withdrawal stimulates efferent pathways in peripheral areas of the body to trigger vasodilation,

bradychardia, and hypotension, eventually leading to loss of both consciousness and postural tone; syncope

(16, 24).

The complex pathophysiology described above is mapped out in Figure 1. It diagrams the VVS

response from time of BS depletion to parasympathetic activation, highlighting the afferent and efferent

pathways. The reason behind beginning after BS depletion is to avoid confusion around the discrepancy of this

mechanism.

Diagnosis

Due to the sporadic nature of VVS, diagnostic testing can be difficult (2). An understanding of the

pathophysiology of the disease is thus crucial in diagnostic measures. To recreate the syncopal response in a

laboratory setting great care must be put towards the recreation of orthostatic pressure and low-extremity

venous pooling, both of which are requirements for the VVS response.

One such diagnostic measure called the Tilt Table Test (TTT) does just that while simultaneously

controlling for syncopal responses in healthy patients. The TTT is an appropriate diagnostic measure when

reviews of medical history, extensive clinical examination, and neurocardiovascular investigation have been

inconclusive (17). The TTT is a highly reproducible diagnostic tool with variable methodologies, although this

variability can sometimes lead to contradictory results; Age has been found to be a confounding variable in

TTT, influencing syncope response type; it is often found that elderly patients display “sudden onset syncope”

without previous history (17).


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Fox, Emma

TTT methodology involves continuous electrocardiographic and blood pressure (BP) monitoring. The

patient is strapped to an electrically controlled tilt table and exposed to varying durations of tilt angles ranging

from 60° and 80° (17). The test continues until a syncopal response (loss of consciousness) is elicited, at

which point the patient is released and data from ECG and BP is gathered and analyzed.

TTT can also be used in the diagnosis of other orthostatic-intolerance diseases such as Postural

orthostatic tachycardia syndrome (POTS), psychogenic syncope, hyperventilation syncope, and carotid sinus

syndrome (17).

Incidence and Prognosis

As mentioned before, VVS is the most prevalent form of syncope, accounting for 21% of all clinical

cases and affecting males and females at roughly similar rates (22). Incidence of syncope appears to increase

with age, with 75% of individuals experiencing roughly one episode of syncope per year (22). In one study, rate

of recurrence of syncope among individuals with a history of syncope was generally higher than the incidence

of a first episode of syncope amongst those without history of syncope, indicating that individuals with syncope

disorders are more likely to have repeat syncope events (22).

The aforementioned study also found that individuals with neurally modulated forms of syncope like

VVS have a 30% higher mortality rate than those with cardiac or non-specific syncope (22). These individuals

have an increased risk of death from stroke, being more than twice as likely to experience a fatal or non-fatal

stroke than individuals with other forms of syncope (22). Other causes of death could not be directly attributed

to the presence of VVS.

Controversy in Research

Sympathetic withdrawal in the VVS response is typically measured by MSNA via an electrode in the

peroneal nerve (24). This withdrawal is seen as the primary step leading to hypotension and loss of


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Fox, Emma consciousness in VVS, yet existing evidence is not substantial enough to prove its critical role. In

several studies, MSNA has been found to drastically decrease as early as 7 minutes prior to syncope despite

central hypovolaemia and hypotension (8, 12, 15). However, some studies have shown sustained MSNA

activity up to and during syncope (24).

This conflicting data puts a significant dent into the progress towards understanding VVS

pathophysiology, challenging the widely accepted notion that total sympathetic withdrawal is the definitive

trigger for hypotension before and during syncope (24). In order to gain a comprehensive understanding of

VVS pathophysiology and to develop more effective treatments, the mechanism for sympathetic withdrawal—

and whether or not its presence is an identifying feature for VVS—should be investigated further.

Conclusion

VVS is the most common form of syncope that affects a significant portion of the adult population. Its

symptoms are usually isolated to the pre-syncope and syncope events, but the disease can have a significant

effect on quality of life. The basic components of the VVS pathophysiology— inappropriate BS, sympathetic

withdrawal, and parasympathetic activation—are backed by several years of laboratory and clinical work, yet

individual components of this mechanism are not yet well understood. This paper highlights key areas of VVS

research including symptoms, pathophysiology, diagnosis, and incidence and prognosis, while also identifying

controversies in current research, suggesting areas in which the field could further investigate.


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Fox, Emma

References

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hemodynamic investigations in the workup of syncope of unknown origin. Pace 11: 1202-14, 1998. 3. Alboni P, Brignole M, Menozzi C, Raviele A, Del Rosso A, Dinelli M, et al. Clinical spectrum of neurally

mediated reflex syncopes. Europace 6: 55–62, 2004. 4. Brignole M, Alboni P, Benditt D, Bergfeldt L, Blanc JJ, Bloch Thomsen PE, et al. Guidelines on

management (diagnosis and treatment) of syncope. Eur Heart J 22: 1256–1306, 2001. 5. Calkins H and Zipes DP. Hypotension and syncope. Braunwald’s Heart Disease 8: 975-983, 2008. 6. Colman N, Nahm K, Ganzeboom KS, Shen WK, Reitsma J, Linzer M, Wieling W, Kaufmann H.

Epidemiology of reflex syncope. Clin Auton Res 14: 9–17, 2004. 7. Fleg JL and Lakatta, EG. Prevalence and significance of postexercise hypotension in apparently

healthy subjects. Am J Cardiol 57: 1380-4, 1986. 8. Fu Q, Verheyden B, Wieling W, and Levine BD. Cardiac output and sympathetic vasoconstrictor

responses during upright tilt to presyncope in healthy humans. J Physciol 590.8: 1839-1848, 2012. 9. 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 17: 1172–1176, 2006.

10. Jacobs MC, Goldstein DS, Willemsen JJ, Smits P, Thien T, Dionne RA, and Lenders JWM. Neurohumoral antecedents of vasodepressor reactions. Eur J Clin Invest 25: 754–761, 1995.

11. Jardine DL, Hamid Ikram, Christopher MF, Rachell Frethey, Sinclair IB, and Ian GC. Autonomic control of vasovagal syncope. Am J Physiol 274 (Heart Circ. Physiol. 43): H2110–H2115, 1998.

12. Jardine DL, Melton IC, Crozier IG, English S, Bennett SI, Frampton CM, Ikram H. Decrease in cardiac output and muscle sympathetic activity during vasovagal syncope. Am J Physiol Heart Circ Physiol 282: H1804–H1809, 2002.

13. Lempert T, Bauer M, Schmidt D. Syncope: a videometric analysis of 56 episodes of transient cerebral hypoxia. Ann Neurol 36: 233–7, 1994.

14. Linzer M, Pontinen M, Gold DT, et al. Impairment of physical and psychosocial function in recurrent syncope. J Clin Epidemiol 144: 1037–43, 1991.

15. Mosqueda-Garcia R, Furlan R, Fernandez-Violante R, Desai T, Snell M, Jaral Z, et al. Sympathetic and baroreceptor reflex function in neurally mediated syncope evoked by tilt. J CLin Invest 99(11): 2736-2744, 1997.

16. Nair N, Padder FA, and Kantharia BK. Pathophysiology and management of neurocardiogenic syncope. Am J Manag Care 9(4): 327-334, 2003.

17. Parry SW and Kenny RA. Tilt table testing in the diagnosis of unexplained syncope. QJM 92(11): 623-629, 1999.

18. Raviele A, Giada F, Menozzi C, Speca G, Orazi S, Gasparini G, Sutton R, Brignole M. A randomized, double-blind, placebo-controlled study of permanent cardiac pacing for the treatment of recurrent tilt-induced vasovagal syncope. The vasovagal syncope and pacing trial (SYNPACE). Eur Heart J 25: 1741 – 1748, 2004.

19. Rea RF, and Thames MD. Neural control mechanisms and vasovagal syncope. J Cardiovasc Electrophysiol 4: 587–595, 1993.

20. Savage DD, Corwin L, McGee DL, et al. Epidemiologic features of isolated syncope: The Framingham Study. Stroke 16: 626-629, 1985.

21. 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 17: 49–54, 2006.

22. Soteriades ES, Evans JC, Larson MG, Chen MH, Chen L, Benjamin EJ, Levy D. Incidence and prognosis of syncope. N Engl J Med 347: 878–885, 2002.


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Fox, Emma 23. Task Force for the D, Management of S, European Society of C, European Heart Rhythm A,

Heart Failure A, Heart Rhythm S, et al. Guidelines for the diagnosis and management of syncope Eur Heart J 30: 2631–71, 2009.

24. Vaddadi G, Esler MD, Dawood T, Lambert E. Persistence of muscle sympathetic nerve activity during vasovagal syncope. Eur Heart J 31(16): 2027-2033, 2010.

Figures

Afferent Pathway (in) Efferent Pathway (out)

Figure 1. A mapping of the complex pathophysiology of VVS, beginning with decreased BS and cardiac mechanoreceptor firing to the medulla oblongata. The afferent input mimics times of increased arterial pressure, and tells the brainstem to trigger the parasympathetic response. Efferent pathways activate this parasympathetic response: vasodilation, hypotension, bradychardia, decreased cardiac output, and eventually, syncope.

Decrease in BS (to the medulla

oblongata)

Myocardial contraction,

Ventricular C fiber activation

Decreased cardiac output

Bradychardia

Hypotension

Vasodilation

Syncope

FoxEmma-NeurocardiogenicSyncope

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