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Quantitation of Presynaptic Cardiac Sympathetic Function with Carbon-11-Meta-Hydroxyephedrine

Division of Cardiology and Departments of Bioengineering and Radiology, Veterans Administration Medical Center, and the University of Washington, Seattle, Washington

Correspondence: For correspondence or reprints contact: James H. Caldwell, MD, Division of Cardiology (111C), Veterans Administration Medical Center, Seattle, WA 98108.

ABSTRACT

The purpose of this study was to validate an axially distributed blood-tissue exchange model for the quantitation of cardiac presynaptic sympathetic nervous system function that could be applied to PET images. The model accounts for heterogeneity in myocardial blood flow, differences in transport rates of ¹¹C-meta-hydroxyephedrine (mHED) across the capillary endothelium and/or neuronal membranes, the virtual volumes of distribution in the interstitial space and neuron and retention of mHED in the neuronal vesicles. Methods: Multiple indicator outflow dilution and residue detection methods were used to measure the kinetics of radiolabeled intravascular space and interstitial space markers and ¹¹C-mHED in isolated perfused rat heart at baseline and during norepinephrine neuronal transporter blockade with desipramine (DMI). The outflow dilution and residue detection data were modeled with a multiple pathway, four-region, axially distributed model of blood-tissue exchange describing flow in the capillary and exchange between regions using permeability-surface area products with units of clearance of milliliters per minute per gram. Meta-hydroxyephedrine may enter the nerve terminal via membrane transport, where it may be sequestered by first-order unidirectional uptake within vesicles. Release of mHED from the vesicles is modeled via exchange with the interstitial space. Results: After intracoronary injection, mHED transport across the capillary endothelium and in the interstitial space closely followed that of sucrose. Subsequently, mHED was retained in the heart, whereas sucrose washed out rapidly. With DMI the outflow dilution curves more closely resembled those of sucrose. Model parameters reflecting capillary-interstitial kinetics and volumes of distribution were unchanged by DMI, whereas parameters reflecting the neuronal transporter process and volumes of distribution in the nerve terminal and vesicular sequestration were markedly decreased by DMI. Application of the model to a pilot set of canine PET images of mHED suggests the feasibility of this approach. Conclusion: Meta-hydroxyephedrine kinetics in the heart can be quantitated using an axially distributed, blood-tissue exchange model that accounts for heterogeneity of flow,reflects changes in neuronal function and is applicable to PET images.

Key Words: sympathetic nervous system • PET • modeling • metahydroxyephedrine • neuronal transporter

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