Vascular endothelial function and blood pressure regulation in afferent autonomic failure.

The hereditary sensory and autonomic neuropathies (HSAN) are a heterogeneous group of genetic diseases associated with abnormalities in peripheral neural fiber development and varying degrees of abnormalities in sensory perception and autonomic regulation.1 Familial dysautonomia (FD; also known as Riley-Day syndrome and HSAN type III) is a recessive trait observed most often in persons of Ashkenazi Jewish heritage and is typically associated with decreased pain and temperature perception and marked autonomic dysregulation manifest as swallowing disorders, gastroesophageal reflux, labile hypertension, and orthostatic hypotension.1–3 The specific genetic defect in almost all cases of FD is a single-point missense mutation in the IKBKAP gene that results in production of a truncated dysfunctional form of its gene product, the I-kappa-B kinase complex–associated protein (IKAP).4 Although the detailed mechanisms have not yet been elucidated, IKAP has been shown to play a critical role in the normal differentiation and survival of peripheral nerves during development.5 The IKAP-mediated defect in neural development is associated with generalized loss of the afferent fibers of the baroreceptor reflex but relative preservation of efferent sympathetic neurons.6 In contrast with patients with acquired forms of baroreflex (afferent) failure associated with selective surgical injury or radiation injury to the ninth and tenth cranial nerves,7 loss of afferent autonomic signaling in patients with FD is generalized and includes afferent input from sympathetic afferents with cell bodies in the dorsal root ganglia.8 This results in a unique phenotype characterized by resting supine hypertension, orthostatic hypotension without tachycardia, and labile hypertension associated with emotional arousal (Figure 1).6,9,10 Figure 1. Autonomic regulatory pathways in familial dysautonomia. Involvement of afferent fibers in IX and X cranial nerves results in loss of sensory input from arterial baroreceptors to the brainstem nucleus tractus solitarius (NTS). Involvement of dorsal root ... The vascular endothelium plays an important role in the normal regulation of peripheral vasomotor tone and blood pressure.11–15 Endothelial production of nitric oxide and other flow-mediated vasoactive substances in conduit arteries is primarily regulated by the magnitude of local changes in phasic shear forces produced by pulsatile blood flow along the blood vessel wall, but modulatory influences of sympathetic activation on endothelial cell nitric oxide production and neuronal sources of nitric oxide also play important regulatory roles.13,16–18 Endothelium-dependent nitric oxide–mediated vasodilation has been reported to be enhanced in patients with acquired forms of efferent autonomic failure when compared with healthy control subjects, but vascular endothelial function in afferent autonomic failure associated with FD has not been previously described.16 Accordingly, this prospective cohort study was conducted to assess vascular endothelial function with brachial artery reactivity testing in FD subjects with congenital afferent autonomic failure and healthy control subjects.