Cardiac pH-Imaging With Hyperpolarized MRI

Abstract

Regardless of the importance of acid-base disturbances in cardiac disease, there are currently no methods for clinical detection of pH in the heart. Several magnetic resonance imaging techniques hold translational promise and may enable in-vivo mapping of pH. We provide a brief overview of these emerging techniques. A particular focus is on the promising advance of magnetic resonance spectroscopy and imaging with hyperpolarized ¹³C-subtrates as biomarkers of myocardial pH. Hyperpolarization allows quantification of key metabolic substrates and their metabolites. Hereby, pH-sensitive reactions can be probed to provide a measure of acid-base alterations. To date, the most used substrates are [1-¹³C]pyruvate and ¹³C-labeled bicarbonate; however, others have been suggested. In cardiovascular medicine, hyperpolarized magnetic resonance spectroscopy has been used to probe acid-base disturbances following pharmacological stress, ischemia and heart failure in animals. In addition to pH-estimation, the technique can quantify fluxes such as the pivotal conversion of pyruvate to lactate via lactate dehydrogenase. This capability, a good safety profile and the fact that the technique is employable in clinical scanners have led to recent translation in early clinical trials. Thus, magnetic resonance spectroscopy and imaging may provide clinical pH-imaging in the near future.

Keywords: acid-base; heart; hyperpolarization; magnetic resonance imaging; myocardium; pH.

Figure 1

Hyperpolarization enables MR spectroscopy and imaging of otherwise undetectable molecules (A). MR signal origins from abundance and polarization of the nuclei of interest. At low temperatures in a strong magnetic field, polarization can be transferred from electrons to MR sensitive nuclei such as ¹³C by microwave radiation. The polarization of the ¹³C-enriched molecule is increased many-fold over thermal polarization. Thereby, the probe and its metabolites become detectable by spectroscopy after intravenous injection. In hyperpolarized pH-imaging, pH is estimated from the equilibrium between the hyperpolarized acid and its conjugate base. These are either in slow exchange, as is the case with bicarbonate and carbon dioxide after injection of hyperpolarized [1-¹³C]pyruvate or ¹³C-bicarbonate, and pH is estimated by the ratio of their peaks (B). Alternatively, they are in fast exchange, and pH can be estimated from the shift in resonance frequency of a single peak (C). This is the case for hyperpolarized zymonic acid, dicarboxylic acids, amino acid derivates, ⁸⁹Y-marked dodecane tetraacetic acid (DOTA) or ethylenediamine tetramethylenephosphonic acid (EDTMP), N-(2-Acetamido)-2-aminoethanesulfonic acid (ACES), ¹⁵N-pyridine derivatives and [1-¹³C]alanine ethyl ester. Using specialized acquisition strategies, pH can be imaged spatially (D). In this example, the rat heart was imaged in-vivo rest and under dobutamine-stress. Hyperpolarized [1-¹³C]pyruvate was used as the probe. This figure is reused and adapted from Lau et al. (21) under an open access Creative Commons CC BY license.