Hyperpolarized 13C MRI of Cardiac Metabolic Remodeling in Heart Disease

Project Summary Abnormalities in cardiac energy metabolism and mitochondrial dysfunction have been implicated in numerous heart diseases such as hypertrophic cardiomyopathy (HCM), diabetic cardiomyopathy, ischemic cardiomyopathy, hypertensive heart disease, HFpEF, systolic and diastolic heart failure. The healthy heart has metabolic flexibility, for example increasing fatty acid oxidation during fasting or increasing glucose oxidation during exercise. In heart disease, there are changes in substrate selection and decreased metabolic flexibility which precede contractile dysfunction. We propose to develop and translate hyperpolarized (HP) 13C-pyruvate MRI for evaluating metabolic remodeling in heart disease. It can quantify metabolic fluxes from pyruvate to acetyl-CoA via pyruvate dehydrogenase (glucose oxidation), and pyruvate to lactate conversion via lactate dehydrogenase for measuring glycolysis/glucose oxidation coupling. No other non-invasive imaging can achieve this. Scanning is rapid, 1-2 minutes, which allows for multiple scans to measure metabolic flexibility under glucose and exercise challenges. In evaluating this technique, we will study HCM patients, the most common inherited cardiomyopathy with a worldwide prevalence of ~1:250 and the leading cause of sudden cardiac death in athletes and otherwise healthy, young individuals. HCM is a metabolic disease, and our pilot studies have demonstrated HP 13C- pyruvate MRI visualizing metabolic remodeling in HCM patients. We propose the following specific aims: 1) Develop HP [1-13C]pyruvate MRI to assess metabolic flexibility and glycolysis-glucose oxidation coupling: scans after fasting and glucose load, rest and after handgrip exercise, and metabolism quantification methods 2) Translate into HCM patients, investigating correlations between metabolism and exercise capacity, substrate availability, and contractile reserve, as well as differences in HCM disease stage, genotype, and phenotype. 3) Examine the effect of 2 HCM treatments, namely recently FDA approved cardiac myosin ATPase inhibitors and exercise-training, on cardiac metabolic flexibility and glycolysis-glucose oxidation coupling, with HP 13C- pyruvate MRI scans at baseline and after 6-8 months of treatment. 4) Develop next-generation HP MRI methods, including refocused imaging methods to improve resolution/SNR, and [2-13C]pyruvate methods for interrogation of TCA cycle flux that is more directly coupled to fatty acid oxidation and reflects mitochondrial function. These will utilize fast acquisitions to freeze heart motion. This translational imaging development will enable unprecedented individualized, regional and global profiles of cardiac metabolism, allowing for preclinical detection, management, and prognosis of heart disease. There is an immediate need for this in HCM, but the techniques developed have broad applicability and impact for examining metabolic defects, abnormalities, and remodeling in heart diseases, with direct translation into the clinic.