title: Robust experiment design for estimating myocardial beta adrenergic receptor concentration using PET.
abstract: Myocardial beta adrenergic receptor (beta-AR) concentration can substantially decrease in congestive heart failure and significantly increase in chronic volume overload, such as in severe aortic valve regurgitation. Positron emission tomography (PET) with an appropriate ligand-receptor model can be used for noninvasive estimation of myocardial beta-AR concentration in vivo. An optimal design of the experiment protocol, however, is needed for sufficiently precise estimates of beta-AR concentration in a heterogeneous population. Standard methods of optimal design do not account for a heterogeneous population with a wide range of beta-AR concentrations and other physiological parameters and consequently are inadequate. To address this, we have developed a methodology to design a robust two-injection protocol that provides reliable estimates of myocardial beta-AR concentration in normal and pathologic states. A two-injection protocol of the high affinity beta-AR antagonist [18F]-(S)-fluorocarazolol was designed based on a computer-generated (or synthetic) population incorporating a wide range of beta-AR concentrations. Timing and dosage of the ligand injections were optimally designed with minimax criterion to provide the least bad beta-AR estimates for the worst case in the synthetic population. This robust experiment design for PET was applied to experiments with pigs before and after beta-AR upregulation by chemical sympathectomy. Estimates of beta-AR concentration were found by minimizing the difference between the model-predicted and experimental PET data. With this robust protocol, estimates of beta-AR concentration showed high precision in both normal and pathologic states. The increase in beta-AR concentration after sympathectomy predicted noninvasively with PET is consistent with the increase shown by in vitro assays in pig myocardium. A robust experiment protocol was designed for PET that yields reliable estimates of beta-AR concentration in a population with normal and pathologic states. This methodology is applicable in general to optimal estimation of parameters in heterogeneous populations.
authors.affiliation: Biomedical Engineering, Case Western Reserve University, Cleveland, Ohio 44106, USA.
authors.forename: Cristian
authors.initials: C
authors.lastname: Salinas
authors.forename: Raymond F
authors.initials: RF
authors.lastname: Muzic
authors.forename: Paul
authors.initials: P
authors.lastname: Ernsberger
authors.forename: Gerald M
authors.initials: GM
authors.lastname: Saidel
mesh_terms: D000319:Adrenergic beta-Antagonists / Q000493:pharmacokinetics*; D000818:Animals; D015415:Biomarkers / Q000378:metabolism; D003198:Computer Simulation; D005260:Female; D005462:Fluorine Radioisotopes / Q000493:pharmacokinetics; D006321:Heart / Q000000981:diagnostic imaging*; D007090:Image Interpretation, Computer-Assisted / Q000379:methods*; D008297:Male; D008954:Models, Biological; D009206:Myocardium / Q000378:metabolism*; D049268:Positron-Emission Tomography / Q000379:methods*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D012107:Research Design; D013552:Swine
chemical_list: D000319:Adrenergic beta-Antagonists; D015415:Biomarkers; D005462:Fluorine Radioisotopes; D011943:Receptors, Adrenergic, beta