Sympathetic Cardioneuropathy in Dysautonomias

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Abstract
The classification of dysautonomias has been confusing, and the pathophysiology obscure. We examined sympathetic innervation of the heart in patients with acquired, idiopathic dysautonomias using thoracic positron-emission tomography and assessments of the entry rate of the sympathetic neurotransmitter norepinephrine into the cardiac venous drainage (cardiac norepinephrine spillover). We related the laboratory findings to signs of sympathetic neurocirculatory failure (orthostatic hypotension and abnormal blood-pressure responses associated with the Valsalva maneuver), central neural degeneration, and responsiveness to treatment with levodopa–carbidopa (Sinemet). Cardiac scans were obtained after intravenous administration of 6-[18F]fluorodopamine in 26 patients with dysautonomia. Fourteen had sympathetic neurocirculatory failure — three with no signs of central neurodegeneration (pure autonomic failure), two with parkinsonism responsive to treatment with levodopa–carbidopa, and nine with central neurodegeneration unresponsive to treatment with levodopa–carbidopa (the Shy–Drager syndrome). The rates of cardiac norepinephrine spillover were estimated on the basis of concentrations of intravenously infused [3H]norepinephrine during catheterization of the right side of the heart. Patients with pure autonomic failure or parkinsonism and sympathetic neurocirculatory failure had no myocardial 6-[18F]fluorodopamine–derived radioactivity or cardiac norepinephrine spillover, indicating loss of myocardial sympathetic-nerve terminals, whereas patients with the Shy–Drager syndrome had increased levels of 6-[18F]fluorodopamine–derived radioactivity, indicating intact sympathetic terminals and absent nerve traffic. Patients with dysautonomia who did not have sympathetic neurocirculatory failure had normal levels of 6-[18F]fluorodopamine–derived radioactivity in myocardium and normal rates of cardiac norepinephrine spillover. The results of 6-[18F]fluorodopamine positron-emission tomography and neurochemical analyses support a new clinical pathophysiologic classification of dysautonomias, based on the occurrence of sympathetic neurocirculatory failure, signs of central neurodegeneration, and responsiveness to levodopa–carbidopa.