This pilot study is the first to prove that JVR is associated with cough syncope. Cough-induced JVR retrogradely transmits venous hypertension into the cerebral venous system, increases cerebral venous pressure or intracranial pressure, decreases CPP, and might consequently reduce CBF during cough [13–17]. There are other known facts supporting the idea that increased cerebral venous or intracranial pressure might play a role in the pathophysiology of cough syncope [26, 27]. One study measured IJV venous pressure during cough in patients with cough syncope and found equalized IJV venous pressure with ABP . In this situation, the net pressure gradient between ABP and venous pressure, the CPP, would decrease and lead to reduced CBF. Another study using transcranial Doppler (TCD) showed a cessation of forward flow in the cerebral artery and diastolic flow reversal during cough-induced syncope . This hemodynamic finding during cough suggests increased impedance in the downstream circulatory pathway, such as in conditions with elevated cerebral venous pressure.
Another novel finding is that higher plasma levels of ET-1 could predict the occurrence of cough syncope. The plasma ET-1 levels have been recognized as a biomarker for predicting vascular endothelial dysfunction . Whether patients with cough syncope have impaired cerebral endothelial function that makes them susceptible to cerebral hypoperfusion is worthy of further study.
The prevalence of JVR shown in a large-population study is around 20-40% . If JVR contributes to the pathophysiology, the question remains why only certain people with JVR have developed cough syncope. There might be different additional factors combining with JVR involved in the pathophysiology of different diseases which are found associated with JVR. Our previous study has demonstrated an interactive effect between JVR and aging on the severity of age-related white matter changes . We suggested that JVR adding age-related cerebral vascular abnormalities precipitated cerebral hypoperfusion in elderly people. In the present study, we have also found that, besides JVR, elevated plasma ET-1 levels might play an additional role in the pathophysiology of cough syncope. This could explain the mismatch between the incidence of cough syncope and VM-induced JVR.
Previous studies showed a fall in systemic ABP during or at the end of coughing, or during the VM in patients with cough syncope, and presumed cough-induced hypotension might play a role in the mechanism [23, 24, 29, 30]. In our study, however, there was no significant difference in mean ABP changes during and at the end of the VM between case and control groups. It is possible that, compared with a virtual cough, the VM had a relatively insufficient intrathoracic elevation and resulted in a non-significant ABP decrement during the VM in the case group. Because of discrepant findings between present and previously reported cough syncope results, [23, 24, 29, 30] we hypothesized that patients with cough syncope might have a higher central venous or intrathoracic pressure at baseline or/and during VM and VM-like activities (e.g. cough), and may induce vasovagal responses via baroreceptor stimulus during cough more easily than people without cough syncope. This could explain why people with cough syncope have both cough-induced hypotension and higher frequency of VM-induced JVR.
There are limitations in our pilot study. We enrolled relatively small sample size (n = 17) and used post-hoc data analysis approach. While simulating the pathophysiology of cough syncope, we evaluated JVR in subjects with supine position instead of upright position, and used VM instead of a heavy cough. Additionally, CBF changes were not analyzed in the present study. Therefore, we could not demonstrate the relationship between JVR/plasma ET-1 levels and CBF changes in our subjects with cough syncope. However, our previous study using transcranial Doppler did reveal an impact of JVR on CBF .