Vasovagal syncope – the electricity, the pump or the input pressure?

“Only if one knows the causes of syncope will he be able to recognize its onset and combat the cause” Maimonides (1135–1204).

Vasovagal syncope, despite its frequent occurrence, particularly in young women, remains an enigma. Many studies have investigated the mechanisms of syncope in healthy individuals and in those prone to faint yet there remains considerable doubt as to what triggers the downward spiral of events that ultimately lead to hypotension and loss of consciousness. For some time it was assumed that faulty sympathetic nervous system (SNS) activity and/or baroreflex function were the prime drivers of syncope and that sympathetic withdrawal, induced by over-stimulated myocardial ventricular afferents, would result in vasodilatation and blood pressure fall. It is now apparent that while the SNS is crucial to maintain adequate vasoconstriction and cerebral blood flow during orthostasis, SNS withdrawal is not a prerequisite for a fall in blood pressure. In fact, the persistence of muscle sympathetic nerve activity (MSNA) has been observed in healthy volunteers submitted to intense lower body negative pressure until the onset of presyncope (Cooke et al. 2009) as well as in recurrent fainters during head-up tilt testing (Vaddadi et al. 2010). The investigation by Fu and colleagues in the current issue of The Journal of Physiology (Fu et al. 2012) reinforces the idea that a loss of sympathetic nerve activity may not drive the cascade by showing that sympathetic withdrawal occurs late, after the onset of hypotension in healthy individuals who developed presyncope during tilting.

A fall in cardiac output (CO) has been proposed by Fu et al. as an alternate driver of syncope. Such a fall in CO prior to syncope has previously been demonstrated by Jardine and colleagues (2002) using the thermodilution method and is confirmed in the current study using a non-invasive pulse pressure-based method (Modelflow). But is this fall cause or effect? Cardiac output is the product of stroke volume (SV) and heart rate (HR) (CO = SV × HR). Stoke volume is dependent on three factors: preload, afterload and contractility. A fall in preload, HR or contractility will reduce CO, but conversely a fall in afterload should result in a rise in CO if preload and contractility remain constant. In the current study participants who had no history of vasovagal syncope but experienced presyncope during head-up tilt were included. Presyncopal participants were divided based on changes in total peripheral resistance (TPR). Cardiac output is seen to fall in both groups, with a greater fall in those with maintained TPR, driven predominantly by a fall in HR. Our interest therefore turns to the group in whom cardiac output falls co-incident with a fall in TPR – a paradox! Is there a fall in cardiac contractility or is the fall in CO driven by reduced preload compared with controls? Unfortunately the present study cannot answer this question; however, the majority of previous studies have demonstrated maintained cardiac contractility during presyncope (Jardine et al. 2002), indicating that a reduction in preload, secondary to venous pooling, is the likely driver.

How can we reconcile the finding of maintained MSNA and apparent excessive venous pooling with no difference in plasma noradrenaline concentration between groups? In this study forearm venous noradrenaline levels are measured rather than the rate of noradrenaline spillover to plasma. A fall in CO will result in reduced plasma clearance of noradrenaline and thus endogenous noradrenaline concentrations are difficult to interpret when CO is changing.

Where to go from here? It would seem we have consensus that MSNA withdrawal is not a requirement for vasovagal syncope. There are thus two possibilities: the first is differential timing of sympathetic activity in different vascular beds. Sympathetic activity to the skeletal muscle only accounts for ∼20% of total sympathetic tone and with sympathetic activity being highly regionalised, vasodilatation in other vascular beds (splanchnic and renal) can occur independently. Jardine and colleagues (2002) postulated that a fall in sympathetic nerve activity in venous capacitance beds results in decreased CO and mild hypotension early in the vasovagal reaction, whereas total sympathetic withdrawal occurs later, resulting in severe hypotension and syncope. The alternate explanation leads us to the recent findings by Vaddadi et al. (2011) that suggested a mismatch between sympathetic nerve firing and noradrenaline responses in individuals with recurrent syncope. In that study MSNA increment was greater during tilt in patients with vasovagal syncope when compared with healthy control participants. In fainters with a low resting systolic blood pressure (≤100 mmHg), there appears to be blunted noradrenaline release, which is associated with reduced tyrosine hydroxylase, the limiting enzyme in noradrenaline synthesis. In those with normal resting systolic blood pressure (≥110 mmHg), blunted noradrenaline responses are associated with increased levels of the noradrenaline transporter, the key protein responsible for noradrenaline reuptake. This implies that while sympathetic withdrawal may not be the key mechanism leading to syncope, aberration in the SNS, at least in its molecular regulation, certainly remains central to vasovagal syncope.

The study by Fu et al. is important for other reasons – as in the study by Vaddadi et al. (2011), it provides further evidence that vasovagal syncope is a heterogeneous condition, and that syncope may have different drivers in different groups, a linear cascade in some but a downward spiral in others. Identifying baseline characteristics that allow us to discriminate between these groups remains a challenge; however, the study of mechanisms and therapies in well-phenotyped patients may well be the escape from the enigma that is vasovagal syncope.