Sympathetic nervous system dysfunction in postural syncope phenotypes

Abstract

Postural syncope is a common disorder characterised by transient loss of consciousness, typically precipitated by prolonged standing. It accounts for 2% of hospital emergency department visits and has high level of morbidity similar to other chronic diseases. The pathophysiology is poorly understood, knowledge within the medical community is limited and treatment is unsatisfactory. Syncope is due to a transient fall in blood pressure which is regulated acutely by the sympathetic nervous system (SNS). This thesis describes detailed investigations of SNS function in patients with recurrent postural syncope. Vasovagal syncope (VVS), the commonest phenotype is subdivided into those patients with normal supine blood pressure (NSBP) and low supine systolic blood pressure (LSBP); a novel classification that has not previously been identified. Patients and healthy controls underwent graded head-up tilt (HUT) with measurement of whole body norepinephrine (NE) spillover using radiotracer methodology. Sympathetic nerve activity (MSNA) was measured in the peroneal nerve as a marker of central nervous system (CNS) sympathetic outflow to skeletal muscle vasculature. Patients with LSBP had high MSNA, while the corresponding release of NE was reduced. This contrasts with NSBP subjects who demonstrated a normal increase in MSNA but reduced NE release. These patients were unable to increase NE at all in response to orthostatic stress. This implies a “mismatch” between the sympathetic neural response to orthostatic stress and the biochemical response, NE release. Reduced NE release rates during orthostatic stress explains the propensity to syncope because the normal compensatory response to gravity medicated venous pooling of blood in the lower limbs during standing is lost. The disparate MSNA levels imply that the underlying mechanisms are different in these 2 groups. To investigate this further, a technique to access sympathetic nerve proteins in human subjects was developed. A subset of patients and healthy controls underwent subcutaneous forearm vein biopsy to extract sympathetic nerve proteins. Tyrosine hydroxylase (TH), the rate limiting enzymes in NE synthesis was reduced to 10% of normal in LSBP subjects, while NSBP subjects were normal. A regional deficiency in TH could explain low NE release rates, low blood pressure and frequent syncope. The norepinephrine transporter (NET) clears NE from the synapse and terminates the effect of the sympathetic neural signal. NSBP patients demonstrated a significant elevation in the expression of NET which could account for low NE release during HUT and thus predispose these patients to syncope. Sympathetic withdrawal is regarded as the final common pathway leading to hypotension during vasovagal syncope. I was able to measure nerve firing during haemodynamic collapse and demonstrate that most patients have preservation of nerve firing, a finding that is at odds with current literature. Postural orthostatic tachycardia syndrome is a perplexing disorder characterised by syncope in the absence of hypotension. The mechanism is unknown and treatment is frequently ineffective. MSNA was markedly elevated while NE release was surprisingly normal. The expression of NET was low which may explain the heightened SNS activation (high MSNA), although it was surprising to see normal NE release rates.