Abstract 535: Mathematical Modeling of Hyperpolarized Pyruvate Metabolism in Human Heart

Abstract

Background: Dissolution dynamic nuclear polarization is a novel method that increases more than 10,000-fold the 13 C signal-to-noise ratio and emerges as a useful tool for detection of molecules much less prevalent than water in the human body. Hyperpolarized [1- 13 C] pyruvate (HP) permits the noninvasive, nonradioactive study of metabolic flux via pyruvate dehydrogenase, a key enzyme in the complex cardiac adaptation to physical activity, energy sources, and in various disease states. The aim of this study is to define an analysis pipeline of multiparametric, non-steady-state, real-time human cardiac magnetic resonance spectroscopic investigations. Methods: HP was infused intravenously into five human subjects. Dynamic spectroscopic data was acquired for [1- 13 C]- pyruvate, 13 C-alanine, [1- 13 C]-lactate, and 13 C-bicarbonate at two consecutive times for each subject. Imaging data were exported into MATLAB. We employed a first-order kinetic model to fit the signal for the hyperpolarized metabolites assuming bidirectional flow between pyruvate and lactate as well as pyruvate and alanine. A gamma variate input function was used to model the initial pyruvate bolus. We also calculated non-parametric values to describe the signal for each metabolite, specifically area-under-curve (AUC) and time-to-peak (TTP). The repeatability analysis was performed using an ANOVA-based method. Results: Rate constants derived from the kinetic model: kPL 0.016 ± 0.008s -1 , kPA 0.012 ± 0.006s -1 , kPB 0.024±0.0095s -1 are of similar order of magnitude to prior studies. The reverse constant for lactate to pyruvate conversion (kLP) is relatively unchanged across the subjects (0.0099±0.0005), and reverse constant for alanine to pyruvate (kAP) conversion is almost negligible (0.0008 ± 0.0012). The model well describes the metabolites signal over time. Within subject repeatability was higher for TTP (lactate: 0.981 ± 0.018) ) than for rate constants (kPL 0.823 ± 0.153) and AUC (lactate 0.697 ± 0.244) with kPB having the lowest repeatability (0.325 ± 0.424) due to a single outlier. Conclusions: We present a real-time pipeline for analysis and modelling of pyruvate metabolism in the human heart and confirm that it is reproducible within the same subject under same conditions.