Role of SNA in the pathophysiology of cardiovascular collapse during syncope: muscle vs. brain

It was with great interest we read the recent findings by Cooke et al. (2009) and related Perspectives article (Joyner, 2009) regarding new insights into the role of efferent sympathetic nerve activity (SNA) in the pathophysiology of cardiovascular collapse during syncope. The authors concluded that abrupt reductions in sympathetic outflow are not an obligatory feature of cardiovascular collapse during syncope or haemorrhage, and that the aetiology of such events has a more complex explanation than merely an ‘empty heart’ and a loss of efferent vasoconstrictor outflow (Cooke et al. 2009). It is well known that syncope refers to a transient loss of consciousness as a result of cerebral hypoperfusion with subsequent spontaneous recovery (Thijs et al. 2004). Therefore, anything that compromises cerebral blood flow (CBF) may jeopardize the ability to maintain consciousness (Van Lieshout et al. 2003). Consequently, brief discussion and synthesis of the new findings by Cooke and colleagues (2009) is warranted, particularly in the context of CBF regulation as the principle underlying cause of syncope.

Although the exact pathophysiological mechanisms leading to the occurrence of syncope are still unknown (Hainsworth, 2004), reflex-mediated factors, physical factors, or a combination of these is thought to be involved (Colman et al. 2004). Traditionally, as outlined in Dr Joyner's Perspectives article, it has been thought that syncope is chiefly caused by hypotension produced by decreased systemic vascular resistance (Barcroft & McMichael, 1944; Lewis, 1932). Recently, this concept has evolved to allow for a precipitous fall in cardiac output to be at least equally responsible for the observed hypotension (Verheyden et al. 2008; Thomas et al. 2009). Both the traditional and more recent theories are limited in that they fail to consider that symptoms and loss of consciousness during syncope are fundamentally due to cerebral hypoperfusion. The view that systemic vascular dynamics are predominantly responsible for the occurrence of a syncopal event is limited in three ways. First, because of effective cerebral autoregulation, arterial blood pressure does not necessarily reflect the cerebrovascular phenomena associated with syncope (Van Lieshout et al. 2003). Second, hypotension as the primary cause of syncope fails to consider the well-documented occurrence of hyperventilation preceding syncope (Lagi et al. 2001; Novak et al. 1998). For example, it has been reported that respiratory instability and hypocapnia impair cerebral perfusion during syncope in patients with orthostatic intolerance (Porta et al. 2008); the degree of hypocapnia at the point of syncope seems to be enough to account for ∼50% of the drop in CBF. Third, falls in cardiac output might directly produce a reduction in CBF. Indeed, despite the classical notion that CBF is maintained over a range of blood pressures, it has been established that CBF is also dependent on cardiac output (van Lieshout et al. 2001; Ide et al. 1998; see Secher et al. 2008 for review). The precise extent to which hypocapnia, cardiac output and hypotension contribute to the reduction in CBF during syncope is not known.

The intriguing findings by Cooke and colleagues (2009) indicate that muscle SNA (MSNA) remains high in a significant number of subjects at pre-syncope and that the normal pulse synchronous characteristics of sympathetic outflow are lost. Because cerebral hypoperfusion is the critical causal factor in syncope, these new data on systemic MSNA activity raise interesting questions regarding cerebral SNA activity leading up to and at the moment of pre-syncope. If changes in cerebral SNA simply parallel those of MSNA, then the presence of high MSNA during profound orthostasis might be interpreted as an important contributing factor to the development of syncope (Levine et al. 1994); recent advances, however, suggest an inverse relationship between systemic and cerebral SNA. For instance, findings from elegant animal studies (Cassaglia et al. 2008, 2009) that utilized the novel continuous recording of SNA in the superior cervical ganglion suggest there is differential control of regional SNA outflow between the brain and other vascular beds; elevations in skeletal muscle SNA may be reflected in reductions in brain SNA (see Ainslie, 2009 for review). It has been shown in lambs that SNA to cerebral vessels increases with acute hypertension (Cassaglia et al. 2008), but not with hypotension, which supports the hypothesis that cerebral SNA serves to protect the brain from hyper-perfusion, rather than regulating the maintenance of basal cerebrovascular tone. In the context of profound orthostatic stress and syncope, the notion that brain SNA might actually be reduced despite elevations in muscle SNA (and related elevations in peripheral vascular resistance) may represent a critical balance in the differential regulation of SNA that serves to optimize global blood flow to the brain. Clearly, the possibility that the balance between cerebral and muscle SNA are key mediators of orthostatic tolerance warrants future study. To examine this hypothesis, measurements of transcranial plasma noradrenaline spillover (Mitchell et al. 2009), as a method for assessing the SNA of the human cerebral vasculature, combined with muscle SNA, would provide mechanistic insight into the potential differential role of SNA in the pathophysiology of syncope and haemorrhage.