VENTRICULAR RECEPTORS ARE NOT THE TRIGGER

Despite the now overwhelming evidence to the contrary, there is still a widely held view that the trigger for vasodilatation and bradycardia is provided by a paradoxical stimulation of cardiac ventricular receptors. The basis of this is the observation by Oberg and Thoren⁷ that some non-myelinated ventricular afferents could be excited when cardiac filling was low and sympathetic efferent nerves were strongly excited. This was said to elicit a Bezold–Jarisch reflex, a powerful depressor response.⁸ This mechanism was proposed despite the fact that any stimulus could only be short lived and baroreceptors would immediately be unloaded. There are several other problems with the ventricular receptor hypothesis. Firstly, only relatively few afferent nerves were excited in this way; most were less active.⁷ Secondly, powerful depressor responses to cardiac receptor stimulation have been shown to occur only to stimulation with foreign chemicals and not to mechanical stimuli. In bypassed near empty dog hearts, sympathetic stimulation did not cause the response.⁹ Thirdly, in humans, the dilator component of the reaction can be provoked following cardiac transplant, and therefore denervation.¹⁰ Finally, also in humans, the heart before syncope is not necessarily nearly empty nor powerfully contracting. It is apparent that some mechanism other than stimulation of ventricular receptors is needed to explain the sudden switch in autonomic activity.

ALTERNATIVE HYPOTHESES

It has long been realised that the brain must have a key role in the initiation of the syncope reaction. This could be by responding to a signal generated elsewhere, or by altering the processing by central pathways, or a combination of both. It is known that blockade of some central neurotransmitters can modify or prevent the onset of a vasovagal reaction. Work on animals has implicated opioid receptors, probably of the δ subtype, and administration of naloxone prevents the vasodilatation in several species.¹¹ This effect of naloxone, however, has not been seen in humans, possibly because of the high doses needed. Another central neurotransmitter that appears to be involved is serotonin. Just before the onset of vasodilatation there is a surge in the serotonin concentration and use of centrally acting serotonin blockade may also prevent the dilatation.¹²

There are several hormonal changes coinciding with the onset of syncope. In particular, plasma vasopressin concentrations show a sudden and dramatic increase.¹¹ Vasopressin, acting peripherally, is a vasoconstrictor agent, but acting centrally it greatly potentiates reflexes and in particular baroreflexes.¹³ If baroreflex sensitivity is greatly increased, relatively low levels of pressure could inhibit sympathetic efferent activity. It may explain an apparent increase in the response of baroreceptors whereby, when patients are returned to supine at the end of a tilt test, a single arterial pulse often seems to induce further vasodilatation and bradycardia, or even asystole.

Another possibility to consider in the initiation of syncope is whether a signal is obtained from a decrease in cerebral perfusion. There have been several claims that there is cerebral vasospasm at that time¹⁴ and speculation that this may initiate a chain of events leading to syncope. However, although a role for cerebral ischaemia cannot be excluded, the occurrence of cerebral vasospasm seems uncertain and may just be a consequence of pressure–flow non-linearity, with a critical closing pressure being approached.¹⁵

The findings by Mercader and colleagues,¹⁶ reported in a recent issue of Heart, are of particular interest as they provide an entirely different approach to the study of the events leading to syncope. They reported that in subjects who developed a vasovagal reaction, there was slow wave electroencephalographic activity from the left cerebral hemispheres. This was not seen in tilt negative subjects nor in a patient with postural hypotension who did not show the vasovagal reaction. It does, therefore, point to a change in central neuronal activity in the period leading to syncope. This work does not provide the answer as to what triggers the response, but it may provide a clue as to where we should be looking.

PRESENT STATE OF KNOWLEDGE

It is easier to state what does not trigger the switch in cardiovascular autonomic activity, than what does. It is certainly clear now that this switch cannot be attributed to stimulation of ventricular mechanoreceptors. Most recent evidence, including the article by Mercader and colleagues,¹⁶ indicates that the mechanism causing the switch lies within the brain itself. Pathways involving opioid and serotonin transmission have been implicated and very large changes in concentrations of cardiovascular acting hormones, and in particular vasopressin, have the potential to modify reflex responses. It is possible that the sensitivity of depressor reflexes becomes abnormally high, leading to a large and unusually prolonged vasodilatation and bradycardia. The switch is likely to involve a complex interaction of neuronal inputs, autonomic output, humoral effects, and ischaemia. However, its nature remains to be elucidated and the mechanism changing vasoconstriction and tachycardia abruptly to vasodilation and bradycardia still remain an unresolved mystery.