PHARMACOLOGIC PROBES IN NEURALLY-MEDIATED SYNCOPE

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The overall goal of these studies is to define the critical pathophysiological features of subtypes of neurally-mediated syncope, a disorder that cause substantial morbidity in young and middle-aged patients. Syncope is a common problem, accounting for as many as 3% of all emergency department visits. While attention has appropriately focused on life-threatening causes, the 30-65% of patients who are categorized as having either "reflex" or "unknown" causes suffer significant capacity as well. The underlying hypothesis of these studies, supported by recent preliminary data, is that patients with neurally- mediated syncope may be categorized by differential abnormalities of autonomic cardiovascular regulation that will predict therapeutic responses. We will address both central and peripheral autonomic mechanisms in hypothesis-driven clinical studies, and follow with a 2- year clinical trial, based on the results of these investigations. We will study patients and matched normal control subjects, assessing autonomic responses directly using recordings of muscle sympathetic nerve activity and determination of norepinephrine spillover and clearance, as well as plasma levels of circulating catecholamines and their metabolites, both at yeast and in response to sympathetic stimulation with well-characterized cortical stressors (modified Stroop and mental arithmetic with interpersonal provocation), physiological stressors (isometric handgrip and cold) and graded head-up tilt. We will also define whether peripheral vascular responses are altered. In patients with reduced sympathetic responses, we will assess alternative approaches to enhancing such responses, using alpha2 receptor antagonism with yohimbine or inhibition of the norepinephrine transporter with desimipramine. We will define the effect of sub-acute (5d) treatment with these agents on central and peripheral alpha-adrenergic responses, and determine whether a withdrawal phenomenon exists. Finally, depending on the results of these studies, we will conduct a 24 month, placebo-controlled, randomized clinical trial of these agents, assessing their efficacy in preventing syncopal episodes, their effect on cardiac rhythm, their possible central side effects, and the potential adverse effects of increased sympathetic tone on cardiac mass and chamber size with echocardiography. These studies will be directly applicable to the evaluation and treatment of patients with these incapacitating disorders.