Serotonin and vasovagal syncope: Too much of a good thing?, 2024, Robert S. Sheldon MD, PhD, FHRS et al

Serotonin and vasovagal syncope
There is ample clinical evidence for the involvement of serotonin signaling in vasovagal syncope. The vasovagal response can be provoked by acute intravenous administration of clomipramine, a specific serotonin reuptake inhibitor, during tilt tests.7,8 This presumably causes an abrupt increase in intrasynaptic serotonin. The effect might also include the stimulation of the presynaptic serotonin 5-HT1A receptor, which can induce bradycardia and vasodilation. The genes for both the serotonin . . .

Serotonin metabolism
Almost all serotonin is synthesized in gastrointestinal enterochromaffin cells, then released and stored in dense platelet granules.14 Relatively little is synthesized centrally. The amino acid precursor to serotonin is tryptophan, which first undergoes hydroxylation by tryptophan hydroxylase to 5-hydroxytryptophan (5-HTP) and then is converted to serotonin by aromatic amino acid decarboxylase. Serotonin is degraded by monoamine oxidase into 5-hydroxy-3-indoleacetaldehyde, then to . . .

Serotonin metabolism and vasovagal syncope
In this issue of Heart Rhythm, Wu and colleagues1 addressed the hypothesis that the metabolic precursors and metabolites of serotonin are involved in vasovagal syncope. They subjected 66 vasovagal syncope patients to the Italian protocol tilt-table test and collected plasma samples at baseline, while upright, and during syncope. They measured serotonin and serotonergic-related metabolites, including its precursor 5-HTP and its major metabolite 5-HIAA, using liquid chromatography–tandem mass . . .

Interpretation
One possible interpretation is that patients prone to faint on a tilt test have a larger pool of 5-HT precursor that can be called on to increase intracellular serotonin for intrasynaptic export that also leaks into the plasma through an unknown mechanism. The unchanged post-tilt serotonin levels could reflect efficient reuptake by the serotonin transporter and rapid metabolic degradation, and the increased post-tilt 5-HIAA would reflect the effective metabolism of serotonin. This is tenuous, . . .

Limitations
There are analytical and conceptual issues to be considered while reflecting on the results. Most important, there are many post hoc analyses, and the correlations are uniformly weak. There is only a limited consideration of the difficulties in dealing with several serotonin compartments: presynaptic, intrasynaptic, plasma, and platelets. Almost all serotonin is synthesized in gastrointestinal enterochromaffin cells, then released and stored in dense platelet granules. What is the . . .

Looking forward
Perhaps it is time to revisit the role of serotonin in vasovagal syncope, both in animal models such as that of Lovelace and coworkers5 and in acute and chronic human studies. The latter will need to reflect the reality of the high penetrance into the population of serotonin-specific reuptake inhibitors. Increasing intrasynaptic serotonin seems to be a good thing, but can we have too much of a good thing?
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