Could 13C MRI assist clinical decision-making for patients with heart disease?

Abstract

Even at this early stage of development, it is clear that the imaging of hyperpolarized (13)C-enriched molecules and their metabolic products offers a new approach to the study of the physiology and disease of the heart. The technology is practical in humans and, for this reason, we consider whether a role in clinical decision-making should motivate further development. The range of interventions available to treat coronary and valvular heart disease is already extensive, and new options are imminent. Yet the appropriate management of patients with left ventricular dysfunction can be challenging because the mechanism of reduced function may be unclear and the ability of the ventricle to respond to therapy may be difficult to predict. Pyruvate is a promising early target for development as a diagnostic agent because it lies at a critical branch point in cardiac biochemistry. The rate of metabolism of hyperpolarized pyruvate to CO(2) relative to lactate may prove to be a useful indicator of preserved mitochondrial function, and therefore provide a specific signal of viable myocardium. Other species including physiological substrates and nonphysiological molecules may provide additional information. Once suitable technology becomes available, it is likely that clinical research will progress quickly. The ability to monitor directly specific metabolic pathways may lead to an improvement in the selection of patients who will benefit from interventions, pharmacologic or otherwise.

Figure 1

Overview of Intermediary Metabolism in the Heart. The myocardium is capable of oxidizing diverse sources of energy such as lactate, glucose, glycogen, ketones and fatty acids of various chain lengths and degrees of saturation. Four groups of reactions, or pathways, support this process: beta-oxidation, glycolysis, the pentose phosphate pathway, and the citric acid cycle. In spite of this complexity, these pathways are linked by a relatively small number of key molecules. Consequently, the rate of appearance of hyperpolarized ¹³C in lactate or CO₂ from [1-¹³C]pyruvate will be sensitive to flux in both beta oxidation and the citric acid cycle. Abbreviations: LAC, lactate; PYR, pyruvate.

Figure 2

A ¹³C NMR spectrum of hyperpolarized [1-¹³C]pyruvate and its metabolic products in isolated rat hearts. This spectrum illustrates typical findings: the [1-¹³C] pyruvate hydrate (not labeled in the figure, at about 179 ppm), [1-¹³C] pyruvate, [1-¹³C]lactate, [1-¹³C]alanine, [¹³C] bicarbonate and ¹³CO₂. The upper panel was taken from a heart supplied solely with hyperpolarized[1-¹³C]pyruvate. The lower spectrum was taken from a heart supplied with both octanoate and HP [1-¹³C]pyruvate. The absence of ¹³CO₂ and bicarbonate was due to suppression of pyruvate oxidation by octanoate. (Redrawn from Reference .)

Figure 3

¹³C NMR Spectra of Isolated Rat Hearts Early (Upper Panel) and Late (Lower Panel) After Reperfusion. Hearts were made ischemic for 10 min. Typically hearts recover quickly after this brief period of ischemia. Oxygen consumption, mechanical function and high energy phosphates returned to normal (data not shown) during that period. However, the ¹³C spectrum was profoundly abnormal, showing elevated lactate and absent bicarbonate or CO₂. The ¹³C NMR spectrum is more sensitive to the metabolic state of the heart than oxygen consumption, mechanical performance or the ³¹P spectrum. The lower panel shows data late after reperfusion. The ability of the heart to generate bicarbonate and CO₂ recovered fully. (Redrawn from Reference .)