Cardiovascular diseases account for more than 30% of all deaths worldwide and many could be ameliorated with early diagnosis. Current cardiac imaging modalities can assess blood flow, heart anatomy and mechanical function. However, for early diagnosis and improved treatment, further functional biomarkers are needed. One such functional biomarker could be the myocardium pH. Although tissue pH is already determinable via MR techniques, and has been since the early 1990s, it remains elusive to use practically. The objective of this study was to explore the possibility to evaluate cardiac pH noninvasively, using in-cell enzymatic rates of hyperpolarized [1-13C]pyruvate metabolism (ie, moles of product produced per unit time) determined directly in real time using magnetic resonance spectroscopy in a perfused mouse heart model. As a gold standard for tissue pH we used 31P spectroscopy and the chemical shift of the inorganic phosphate (Pi) signal. The nonhomogenous pH distribution of the perfused heart was analyzed using a multi-parametric analysis of this signal, thus taking into account the heterogeneous nature of this characteristic. As opposed to the signal ratio of hyperpolarized [13C]bicarbonate to [13CO2], which has shown correlation to pH in other studies, we investigated here the ratio of two intracellular enzymatic rates: lactate dehydrogenase (LDH) and pyruvate dehydrogenase (PDH), by way of determining the production rates of [1-13C]lactate and [13C]bicarbonate, respectively. The enzyme activities determined here are intracellular, while the pH determined using the Pi signal may contain an extracellular component, which could not be ruled out. Nevertheless, we report a strong correlation between the tissue pH and the LDH/PDH activities ratio. This work may pave the way for using the LDH/PDH activities ratio as an indicator of cardiac intracellular pH in vivo, in an MRI examination.
Bibliographical noteFunding Information:
Horizon 2020 Framework Programme FP7, European Research Council, Grant/Award Number: 338040; Horizon 2020 Framework Programme, Grant/Award Number: 667192; Israel Innovation Authority, Grant/Award Number: 63361; Israel Science Foundation, Grant/Award Number: 1379/18; Israel Ministry of Science and Technology, Grant/Award Number: 3‐15892 Funding information
We thank Dr. Talia Harris for assistance with selective pulses applications. This project has received funding from the European Research Council (ERC) under grant agreement no. 338040, the European Union's Horizon 2020 research and innovation program under grant agreement no. 667192, the Israel Innovation Authority, KAMIN Incentive program, grant agreement no. 63361, the Israel Science Foundation under grant agreement no. 1379/18, and the Jabotinsky Scholarship of the Israeli Ministry of Science and Technology for Applied and Engineering Sciences for Direct PhD Students no. 3–15892 for D.S.
© 2020 John Wiley & Sons, Ltd.
- hyperpolarized 13C MR
- imaging agent
- magnetic resonance spectroscopy
- metabolic imaging