Muscle Sympathetic Nerve Activity and Syncope

Fig. 5.1

Pathway of arterial baroreflex. The square area is illustrated in Fig. 5.2 in detail (See the text for the mechanism)

Fig. 5.2

Pathway of arterial baroreflex in the brain stem (See the text for the mechanism and abbreviations)

The sympathetic nervous system is also called the thoracolumbar nervous system. The cardiovascular center is situated at the rostral ventrolateral medulla (RVLM), and the axons of the premotor neurons descend to the intermediolateral nucleus (ILM), where synapse to preganglionic neurons, which are myelinated B-fibers. The sympathetic preganglionic neurons exit the spinal cord as the white rami from the first thoracic nerve (T₁) to the second/third lumbar nerve (L_2/3) and enter the sympathetic trunk or chain, which is also known as the paravertebral ganglion. The sympathetic trunk forms the superior, middle, and inferior cervical ganglia, while the inferior ganglion often fuses with the first thoracic ganglion to form the stellate ganglion (in 80 % of cases) and travels downward to the fifth sacral ganglion, with which the stellate ganglion, the cardiac sympathetic innervation of T₁–T₃, and the systemic vasoconstrictive innervation to the arterioles of the resistant vessels are directly involved [11, 22, 24].

5.4 Parasympathetic Nervous System (Figs. 5.1 and 5.2)

The parasympathetic nervous system is also called the craniosacral nervous system, which exits from the brain stem as the oculomotor (CN III), facial (CN VII), and glossopharyngeal (CN IX) nerves, innervating the ciliary, pterygopalatine, and otic ganglia, respectively, as well as the vagus nerve. The vagus nerve shares 85 % of the entire parasympathetic nervous system, and its innervation is distributed to the dura mater, auricle, upper pharynx, lung, heart, liver, kidney, stomach, small intestine, and transverse colon down to the splenic flexure. The parasympathetic nerve fibers exiting from the S₂ to S₄ innervate defecation and urogenital organs including the descending colon, rectum, kidney, bladder, prostate, and genital organs. Among these parasympathetic innervations, direct blood pressure control was shown to involve the cardiac branch of the vagus [11, 22, 24].

5.5 Autonomic Control of the Cardiovascular System

Baroreceptors are situated at the carotid sinus and the aortic arch; they monitor the arterial pressure and transmit information on this pressure to the central nervous system. Upon extension of the arterial wall by raising of the blood pressure, the baroreceptors (stretch receptors) generate an impulse depending on the arterial pressure via the glossopharyngeal nerve (CN IX) from the carotid sinus and via the vagus nerve (CN X) from the aortic arch and transmit the signals to the nucleus tractus solitarius (NTS) in the medulla [13–16].

From the NTS, excitatory information is sent via the glutamatergic neurons to the caudal ventrolateral medulla (CVLM), where the inversion of positive and negative signs is executed. The CVLM then transmits GABAergic (using γ-amino butyric acid as a neurotransmitter) neurons to the rostral ventrolateral medulla (RVLM). The topographical regional differentiation has been established [4].

The RVLM neurons are considered to be premotor neurons for the preganglionic efferent neurons whose cell bodies are situated in the intermediolateral nucleus (IML), with synapses to the preganglionic B-fiber neurons, and which exit from the spinal cord as white rami.

In contrast, input from NTS to the nucleus ambiguus and the dorsal nucleus of the vagus modulates the activity of the vagal nerve, innervating the heart and presphincters of the resistant vessels and causing decreases in heart rate and cardiac contractility.

As for the sympathetic efferent pathway, the cardiac sympathetic activity and the activity of muscle sympathetic nerves innervating skeletal muscles play a role in blood pressure regulation. Muscle sympathetic nerve activity (MSNA) can be recorded microneurographically from human peripheral nerves in situ, which is the only baromodulatory sympathetic nerve activity directly recordable in humans (Fig. 5.1). The techniques to record MSNA are described elsewhere [20].

These pathways provide a negative feedback mechanism to suppress the sympathetic nerve activity, while the vagus nerve activity is activated when blood pressure rises, and facilitate the sympathetic nerve activity and suppress the vagus nerve activity when blood pressure drops.

5.6 The Autonomic Nervous System and Syncope

How is the autonomic nervous system involved in the onset of syncope? It is primarily responsible for sympathetic responses toward environmental challenges. The most frequent challenge triggering syncope might be a postural change (Fig. 5.3). Syncope or fainting associated with orthostatic challenge includes vasovagal syncope (or in a wider sense, neurally mediated syncope) and orthostatic syncope (or orthostatic intolerance). The symptoms of these two situations seem to be the same, but the pathophysiology is different; they involve opposite directions of pathways of the autonomic nervous system.

Fig. 5.3

Responses of microneurographically recorded muscle sympathetic nerve activity during orthostatic challenge. MSNA is sparsely discharged in a supine position, but is remarkably enhanced as the tilt angle becomes large

In the following sections, syncope from the perspective of the autonomic nervous system is described, based on the premise that no structural or conduction disorder is present in the heart.

5.7 Vasovagal Syncope (or in a Wider Sense, Neurally Mediated Syncope)

The concept of vasovagal syncope was first proposed by Lewis in 1932, with primary symptoms of hypotension and bradycardia. Vasovagal syncope is triggered by an exaggerated sympathetic response to a situation; in other words, sympathoexcitation precedes the onset.

The Bezold-Jarisch reflex plays an important role in the onset of this type of syncope. This reflex is generated by the cerebral hypoperfusion due to vagal-activation-mediated sympathosuppression for the protection of the myocardium. This vagal activation may be caused by hyperactivity of the left ventricular wall, which activates the stretch receptors in the wall and trabeculae, and in turn the C-fiber afferents to NTS, which triggers bradycardia and decreased myocardial contractility [27].

Several factors are known to exacerbate and accelerate vasovagal syncope, including (1) fatigue, dehydration, and hypovolemia due to hemorrhage, followed by reduced venous return; (2) blood shift and pooling in the lower body; (3) hypersensitivity of the stretch receptors in the left ventricular wall; and (4) fear, emotional stress, and reaction to pain [6]. Among these, (3) is the trigger that is considered to be essential for the Bezold-Jarisch reflex.

An analysis of the polygraph of vasovagal syncope indicated that there are three phases in the onset of vasovagal syncope. The changes during 60° head-up tilt and polygraph trace (Fig. 5.4) and flow charts are described below (Fig. 5.5).

Fig. 5.4

Polygraph of vasovagal syncope. Over the course of syncope progression in three stages, syncope onset develops at stage III

Fig. 5.5

Progression of vasovagal syncope from stage I to stage III

5.7.1 Stage I: Oscillation Phase [14, 17, 28, 29]

In stage I, the sympathetic nerve activity (MSNA) and blood pressure display an oscillation pattern with the levels being well maintained. The time lag from MSNA discharge to blood pressure rise by the constriction of arterioles is approximately 4–5 s, while the time lag from the blood pressure rise to vasodilatation by the suppression of sympathetic nerve activity is approximately 1 s from the descending pathway in the medulla oblongata to the peripheral vasodilating sphincter muscles via the synapse in the sympathetic chain to the postganglionic C-fiber, the time delay from the baroreceptor to the recording site of microneurography. The sympathetic discharge induces a blood pressure rise. This double feedback mechanism oscillates to maintain the blood pressure. In stage I, blood pressure wave and heart rate oscillate with a frequency of 0.1 Hz (10 s period), and the low frequency component (LF) of heart rate variability is enhanced. This phase includes mutual increases in both sympathetic and vagal activities.

5.7.2 Stage II: Imbalance Phase [14, 15, 17, 19, 28]

At this stage, venous return is reduced due to the failure to compensate for the enhanced venous pooling, which makes blood pressure maintenance difficult. The tidal volume is raised to increase the venous return. Failure of the double feedback mechanism arises with the enhanced power of the high-frequency (HF) component of the blood pressure wave and heart rate variability. The falling blood pressure due to decreased stroke volume cannot be compensated for by only peripheral vasoconstriction, inducing an extremely elevated heart rate. This tachycardia compensates for the reduced stroke volume, which could not be compensated for by decreased venous return or circulatory blood volume. In this state, cardiac echography sometimes reveals parallel movement of the interventricular septum and the left ventricular wall, which is called “paradoxical movement.” It is estimated that this state involves the sympathetic nerve activity being overwhelmed by the parasympathetic nerve activity, and the reciprocal relationship between the diastolic blood pressure and MSNA, denoting the baroreflex function, disappears late in this phase.

5.7.3 Stage III: Catastrophe Phase [14, 15, 17]

In spite of the effort to maintain the blood pressure by an increased heart rate, the stage transitions to stage III, when a sudden heart rate drop with the cessation of MSNA is observed, resulting in an immediate fall in blood pressure. Some patients experience cardiac arrest simultaneously with cold sweat, nausea, blackout, and loss of consciousness. Dominant activation of parasympathetic nerve activity occurs concomitantly with sympathosuppression. In “neurally mediated syncope,” this stage corresponds to the classification of cardiosuppressive, vasosuppresive, and mixed types, which are based on whether the suppressive drive is dominant over cardiac or vasomotor sympathetic drives or both.

Therefore, sympathoactivation is observed, followed by sudden tachycardia, which triggers the onset of vasovagal syncope or neurally mediated syncope.

5.8 Burst Property Change During the Progression of Syncope [14]

As the hypotensive attack began, the subject complained of nausea and exhibited pallor with sweating, and there was a disappearance of pulse synchrony of MSNA and an elongated burst duration (Fig. 5.6). After complete recovery, the electrode was reinserted to obtain an MSNA burst at a satisfactory level.

Fig. 5.6

Changes in MSNA in fainting: (a) when the subject is conscious, (b) when the subject complains of a fainting sensation, (c) when the subject complains of nausea and becomes pale with sweating, (d) when the subject loses consciousness, and (e) when the subject is laid down after the reinsertion. From (a to e), upper trace is original MSNA, middle trace is full-wave rectified and integrated MSNA, and lower trace is electrocardiogram. (b, c) Are prefaint states, and (d, e) are fainting states. In (b) burst duration became elongated, although pulse synchrony is still maintained. In (c–e), pulse synchrony disappears and burst duration becomes elongated more and more as the fainting proceeds

The burst duration of a typical subject in a conscious state (stage I) was 246 ± 32 ms, whereas it was elongated to 556 ± 157 ms in prefainting (stage II) and further elongated in the fainting state (stage III) to 771 ± 123 ms (Fig. 5.7). After complete recovery of consciousness, it recovered to a fairly constant value of 303 ± 51 ms. The averaged burst duration in the six subjects was significantly reduced by the fainting event from 279 ± 52 ms in a conscious state to 619 ± 92 ms in prefainting, 834 ± 78 ms in fainting, and recovered to 349 ± 59 ms (Fig. 5.8, F = 75.793, p < 0.0001). The reflex latency in a conscious state in a typical subject was 1,062 ± 41 ms. When the subject complained of a fainting sensation and nausea (presyncopal state), it became shortened but scattered to 740 ± 139 ms, becoming further shortened and scattered to 723 ± 289 ms in the fainting state (Fig. 5.7). The standard deviations of reflex latencies in the six subjects were significantly increased by the fainting event from 57 ± 12 to 182 ± 33 ms in prefainting, 357 ± 58 ms in fainting, and recovered to 59 ± 8 ms (Fig. 5.8, F = 102.329, p < 0.0001).