Assessing mitochondrial respiration in isolated hearts using (17)O MRS.

The application of (17)O MRI and MRS for the evaluation of cardiac mitochondrial function has been limited because of the challenge of detecting metabolic H(2)(17)O in the vast background of naturally abundant H(2)(17)O. In this study, we have developed a direct (17)O MRS approach to examine the feasibility and sensitivity of detecting metabolically produced H(2)(17)O in isolated rat hearts perfused with (17)O(2)-enriched Krebs-Henseleit buffer containing normal (1.5 mm) and high (2.5 mm) calcium (Ca(2+)) concentrations to induce high workload. Consistent with increased workload at high Ca(2+) concentration, the measured myocardial oxygen consumption rate (MVO(2)) increased by 82%. Dynamic (17)O MRS showed an accelerated increase in the H(2)(17)O signal at high Ca(2+) concentration, suggesting increased mitochondrial production of H(2)(17)O in concordance with the increased workload. A compartment model was developed to describe the kinetics of H(2)(17)O production as a function of MVO(2). The myocardial (17)O(2) consumption rate (MV(17)O(2) was determined by least-squares fitting of the model to the NMR-measured H(2)(17)O concentration. Consistent with the measured MVO(2), the model-determined MV(17)O(2) showed a 92% increase at high Ca(2+) concentration. The increase in metabolic activity at high workload allowed the balance between ATP production and utilization to be maintained, leading to a similar phosphocreatine to ATP ratio. These results demonstrate that dynamic (17)O MRS can provide a valuable tool for the detection of an altered metabolic rate associated with a change in cardiac workload.