Evaluation of the myocardial autonomic nervous system has previously been limited to animal models because of the unavailability of noninvasive methods, which could be used in humans. With the advent of radiopharmaceuticals which specifically delineate presynaptic and parasympathetic nerve terminals, integrity of the autonomic nervous system can be quantitatively assessed using positron emission tomography (PET). Animal studies have validated these new imaging approaches and initial clinical studies have provided excellent image quality necessary for the regional definition of tracer kinetics. This proposal will focus on the clinical application of neuronal imaging using PET in cardiac disease states which are known to affect the autonomic innervation of the heart. These studies will provide the base for the possible clinical application of these tracer approaches in the therapeutic management of patients. Initial studies with the catecholamine analogue C-11 hydroxyephedrine as well as parasympathetic tracer F-18 benzovesamicol will focus on the definition of tracer kinetics in the normal and denervated human heart. Incidence and time course in reinnervation of the human transplanted heart will be investigated since preliminary data suggest regional catecholamine uptake sites in patients with remote cardiac transplant. Longitudinal studies in patients with diabetic neuropathy using tracers for the sympathetic as well as the parasympathetic nervous system may elucidate the time course and natural history of autonomic dysfunction in this patient population. The major effort of this proposal will focus on the definition of the sympathetic and parasympathetic nervous system in patients with dilated cardiomyopathy. Regional myocardial kinetics of C-11 hydroxyephedrine will be used to quantitate the catecholamine storage capacity of the presynaptic neuron. Scintigraphic measurements will be correlated with regional electrophysiologic parameters such as effective refractory period and fibrillation threshold using electrophysiologic mapping techniques during open heart surgery. These functional measurements will be supplemented by tissue analysis for catecholamine content and histopathological integrity of the neuronal structures in corresponding sites. In addition, patients undergoing cardiac transplantation will undergo PET imaging prior to this procedure and the scintigraphic results will be compared with regional tissue analysis of the ex-planted cardiomyopathic heart using biochemical and autoradiographic techniques. This integrated approach using imaging technologies, electrophysiologic testing, and in-vitro tissue characterization including autoradiography will represent an unique definition of the autonomic nervous system in patients with various degree of dilated cardiomyopathy.
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