Biochemical mechanism of VVS in vitamin B12/folate deficiency
The pathophysiology of VVS is poorly understood, and there are ongoing efforts to address this gap in order to introduce novel treatment strategies for this potentially debilitating condition.30 According to a hypothesis,31 VVS is characterized by an over activation of the parasympathetic nervous system in response to an exaggerated activation of the sympathetic nervous system, demonstrated by increased serum levels of catecholamines.14-19Patients with VVS have normal resting serum levels of catecholamines; nevertheless, their serum catecholamines start to rise in response to head-up tilting, a similar situation to an actual syncopal episode. 14-19Ineffective metabolism of released catecholamines is suggested to play a key role in the increased levels of these metabolites.21 There are two main pathways for the metabolism of catecholamines, catechol-O-methyltransferase (COMT)- and monoamine oxidase (MAO)-dependent pathways. The COMT pathway requires S-adenosyl methionine (SAM), of which normal levels necessitate sufficient serum levels of vitamin B12 and folate.20 In fact, vitamin B12 and folate are cofactors for the degradation of catecholamines. Hence, vitamin B12 or folate deficiency can decrease SAM, decrease COMT-dependent degradation of catecholamines, increase serum levels of catecholamines in response to VVS triggers, and lead to syncope.