Discussion
In this study, we report that resting HR in patients with vasovagal reflex syncope during tilt testing was lower compared with those who had postural orthostatic tachycardia syndrome and with those whose tests were negative. Furthermore, MR-proANP was significantly higher among those with VVS compared with POTS, and MR-proANP was inversely related to supine HR. When these variables were combined, patients with both a resting HR <70 bpm plus MR-proANP levels >45 pm/L had an OR of approximately four times for reflex syncope compared with subjects without any of these criteria; the OR increased to 22 if male sex was also included as a criteria in the model. We also showed that patients with OH had lower resting renin, while patients with POTS demonstrated pronounced increase in norepinephrine. Patients with POTS also demonstrated greater increase in CT-proAVP during HUT than patients with negative HUT, however, not compared with any other group. Finally, we have observed that patient’s history and symptoms during syncope may not be specific for any diagnosis.
Our previous reports suggested that lower values of MR-proANP were predictive of both VVS12 and orthostatic tachycardia9 in the general syncope population. In this study, the head-to-head comparison between age-matched younger patients with VVS and patients with POTS demonstrated that lower MR-proANP is more suggestive of POTS.
The finding of lower resting HR among patients with VVS implies higher vagal tone and/or a lower sympathetic tone affecting the heart at rest compared with patients with a negative test. Interestingly, this difference in HR seems to be attenuated during orthostatic challenge, which may be explained by either a marked vagal withdrawal or a more pronounced increase in adrenergic drive. For obvious reasons, patients with POTS demonstrated greatest increase in HR during HUT, outperforming that of VVS positive and negative HUT but the difference between patients with VVS and negative HUT was also significant. However, although orthostatic increase in HR in POTS is pathognomonic for this syndrome, less is known about chronotropic response in patients with VVS compared with normal subjects. Our reference group with negative HUT do not represent normal subjects, but they are autonomically more integrated and do not demonstrate the hypotensive tendency usually detected by tilt testing.17 Consequently, the attenuation of difference in HR between patients with VVS positive and negative HUT during orthostatic challenge may be due to counteracting the hypotensive tendency in standing in the former by increasing HR and cardiac output. Interestingly, epinephrine elevation during early HUT phase did not differ between the groups, an observation that suggests a baroreceptor-mediated vagal withdrawal as the main mechanism of HR increase in patients with positive VVS.
Compared with patients with POTS, MR-proANP was significantly higher among those with VVS, which corroborates our previous findings of decreased ANP in postural tachycardia.9 Also, we found that higher MR-proANP was inversely related to resting HR. Thus, patients with VVS show lower HR, which is in turn associated with higher ANP. The most important stimulus for ANP secretion is stretching of atrial walls, which takes place with a high blood volume and raised atrial pressure.18 19 One could hypothesise that the lower resting HR of pateints with VVS would lead to greater filling of these cardiac chambers during the cardiac cycle, which in turn would trigger increased release of ANP in these patients. On the contrary, patients with POTS may have underfilling of the atria, leading to reduced ANP. Whether higher resting MR-proANP levels may in itself also predispose to a vasovagal reaction during orthostatic stress remains to be determined.
Current clinical guidelines3emphasise the need for careful history taking when evaluating patients with unexplained syncope. VVS is by far the most common cause of syncope in young patients2 3 and it is suggested by some authors that VVS may be diagnosed solely by careful history taking.20 In this study, none of the clinical features such as the total number of attacks, how many years ago the first syncope occurred, dizziness on standing and palpitations or typical prodrome preceding syncope was highly specific for any diagnosis. Of interest, the proportion of patients with POTS that reported palpitations was low (3 of 10), and this proportion was the same among patients with VVS. Furthermore, even though the proportion of patients reporting dizziness on standing was slightly lower among VVS compared with other diagnoses, 6 of 10 patients with VVS still reported this symptom. The history is without doubt a powerful tool in diagnosing syncope, in particular when taken by a trained expert.21 In this study, patients were asked to fill a standard questionnaire prior to tilt testing. Self-reported history obtained by filling a questionnaire is similar to history taking by a non-expert yielding around 60% accuracy.22 While it has been shown that a level of accuracy when an expert takes history is very high, as much as 90%.23 We believe that these results indicate that tilt testing with non-invasive beat-to-beat monitoring should be considered in unexplained syncope associated with symptoms of orthostatic intolerance, especially in the absence of a syncope expert. When an expert is available, tilt testing may be seen as a diagnostic tool for confirmation of diagnosis and an additional test in unresolved cases.
VVS and POTS are diagnoses that are very common in young subjects, yet the treatment strategies for these diagnoses may differ6 and an accurate diagnosis is essential when attempting to prevent syncope recurrence. Since patients with VVS and POTS seem to show opposite patterns of both haemodynamic factors (resting HR lower among patients with VVS) and neuroendocrine markers (resting MR-proANP lower in POTS), we suggest the possibility that resting HR and MR-proANP, easily assessed through commercially available test kits, may be considered as additional tools in the evaluation of young patients with unexplained syncope. Moreover, the lower HR in patients with VVS would tend to make them unsuitable for treatment with β-blockers, a strategy, which has failed in randomised trials on prevention of syncope recurrences.3 The lower resting HR in patients with VVS may be closer to ‘normal’ as corroborated by other data from the Malmö population. In the Malmö Preventive Project, 8370 healthy individuals aged 27–40 years had resting HR of 67±10 bpm,24 similar to VVS in our study. Consequently, patients with VVS can be considered normal except when they are having reflex syncope. In contrast, POTS and OH are patients with persistent manifestations of their condition, expressed by abnormal adrenergic activation or vagal withdrawal at rest and higher HR. Patients with negative HUT are, on the other hand, a non-homogenous group, possibly with over-representation of anxiety disorders, which would explain the higher pretest HR. The fact that the proportion of men is higher among patients with VVS than among patients with POTS is consistent with the well-known fact that POTS is more often diagnosed in women.6
Among other observations, lower renin in OH is supported by earlier studies in diabetic patients with OH,25 but has not been recently confirmed11 in very young subjects and thus warrants further study, possibly including other components of renin-angiotensin system. In contrast, a significant increase in norepinephrine during HUT in patients with POTS can be considered confirmatory, as it has been previously demonstrated in several studies.9 11 26 The finding of a greater increase in AVP during orthostasis in patients with POTS may have physiological basis in that a low blood volume is a well-known strong stimulus for AVP release. Of possible clinical relevance relating to these findings, copeptin levels have been suggested to predict the outcome of treatment with midodrine hydrochloride27 and β-blockers in children with POTS.28
Our study has some limitations that should be mentioned. First, no control subjects without a history of syncope and/or orthostatic intolerance were included. However, the fact that only patients with unexplained syncope and/or orthostatic intolerance referred for further evaluation were included also makes the results clinically relevant. Second, the neuroendocrine data were measured at rest and at 3 min during HUT only. Further changes in these parameters might have occurred later during HUT, as well as after syncope. Third, there is an overlap between POTS and VVS in that many patients with POTS also experience syncope by VVS. In our study, 47 out of the 72 patients with POTS (65%) also had VVS during HUT. However, as treatment in these patients should probably be directed to the precipitating factors in form of their main diagnosis including the postural tachycardia and orthostatic intolerance rather than the VVS per se, we still find the distinction between ‘pure VVS’ and POTS (±VVS) important for successful treatment outcome. Fourth, the strict cut-off for HR in the diagnosis of POTS means that some patients with haemodynamic findings that are suggestive of, but not diagnostic for, POTS may be classified as either VVS or negative HUT. Finally, even though the use of medications influencing HUT results was very low in the study population should not affect results on the group level, such medications may of course have affected test results for a small number of individual patients.
In conclusion, we have shown that among young patients with unexplained syncope, patients with VVS are more likely to be men, have lower HR and higher MR-proANP at rest than patients with POTS. We propose that these parameters might be taken into account during the initial evaluation of unexplained syncope in young patients.