We conducted patient-oriented research in clinical neurocardiology. Studies focused on etiology, diagnosis, and pathophysiology of disorders involving catecholamine systems, which use norepinephrine (NE), adrenaline (ADR), or dopamine (DA) as the effector chemicals. The sympathetic nervous system (SNS) regulates cardiovascular function by releasing NE from the nerves as a neurotransmitter. The adrenomedullary hormonal system releases ADR into the bloodstream as a hormone. Loss of DA in a particular brain pathway is known to cause the movement disorder in Parkinson?s disease (PD). Patients were studied who had PD with a fall in blood pressure while standing (orthostatic hypotension, OH); had chronic orthostatic intolerance with tilt-induced loss of consciousness (neurocardiogenic syncope); or had pheochromocytoma, a clinically important tumor that produces catecholamines. Patients with PD+OH all had poor reflexive regulation of the SNS and loss of sympathetic nerves in the heart, confirming PD+OH as not only a movement disorder but also a neurocardiologic disorder. Patients with familial PD from mutation of the gene encoding alpha-synuclein, or from excessive expression of the normal gene, had a loss of cardiac sympathetic nerves. These findings indicate that in PD, both the movement and neurocardiologic disorders reflect synucleinopathy. In contrast, baboons with chronic PD from administration of the neurotoxin, MPTP, had intact cardiac sympathetic innervation. Patients with tilt-induced neurocardiogenic syncope characteristically had antecedent """"""""sympathoadrenal imbalance"""""""" (SAI), with high ADR levels and loss of vascular tone in skeletal muscle before the syncope, leading us to propose that SAI may contribute to a positive feedback loop that leads cardiovascular collapse within seconds to minutes. In the diagnostic evaluation of pheochromocytoma, we showed that plasma levels of metanephrines, metabolites of NE and ADR made in the tumor, provide a uniquely and virtually perfectly sensitive screening test. We also completed a large prospective study validating 6-[18F]Fluorodopamine positron-emission tomographic scanning for diagnostic localization of pheochromocytoma. New protocols based on these findings will characterize comprehensively the central neural and autonomic abnormalities in PD+OH and familial PD; assess the efficacy of non-selective beta-adrenoceptor blockade in preventing tilt-induced neurocardiogenic syncope; and relate clinical and neurochemical phenotypes to results of microarray studies of gene expression in human pheochromocytoma tissue.
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