Hyperpolarized 13C Magnetic Resonance Reveals Early- and Late-Onset Changes to in vivo Pyruvate Metabolism in the Failing Heart

Abstract

Aims: Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized 13C magnetic resonance (MR), in which 13C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [13C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease. Methods and results: Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-13C]pyruvate was administered intravenously, and 13C MRS monitored [13C]glutamate production; 31P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-13C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [13C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [13C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [13C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively. Conclusion: Despite early changes associated with cardiac energetics and 13C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart’s capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized 13C MR may be important to characterize metabolic changes that occur during heart failure progression.