An intact small animal model of myocardial ischemia-reperfusion: Characterization of metabolic changes by hyperpolarized 13C MR spectroscopy

Abstract

Hyperpolarized carbon-13 magnetic resonance spectroscopy (13C MRS) enables the sensitive and noninvasive assessment of the metabolic changes occurring during myocardial ischemia-reperfusion. Ischemia-reperfusion models using hyperpolarized 13C MRS are established in heart preparations ex vivo and in large animals in vivo, but an in vivo model in small animals would be advantageous to allow the study of reperfusion metabolism with neuroendocrine and inflammatory responses intact with the option to perform a greater number of experiments. A novel intact rat model of ischemia-reperfusion is presented that incorporates hyperpolarized 13C MRS to characterize reperfusion metabolism. Typically, in an in vivo model, a tissue input function (TIF) is required to account for apparent changes in the metabolism of injected hyperpolarized [1-13C]pyruvate resulting from changes in perfusion. Whereas the measurement of a TIF by metabolic imaging is particularly challenging in small animals, the ratios of downstream metabolites can be used as an alternative. The ratio of [13C]bicarbonate:[1-13C]lactate (RatioBic/Lac) measured within 1–2 min after coronary release decreased vs. baseline in ischemic rats ( n = 10, 15-min occlusion, controls: n = 10; P = 0.017 for interaction, 2-way ANOVA). The decrease in oxidative pyruvate metabolism [RatioBic/Lac(Ischemia)/RatioBic/Lac(Baseline)] modestly correlated with area at risk ( r = 0.66; P = 0.002). Hyperpolarized 13C MRS was also used to examine alanine production during ischemia, which is observed in ex vivo models, but no significant change was noted; metrics incorporating [1-13C]alanine did not substantially improve the discrimination of ischemic-reperfused myocardium from nonischemic myocardium. This intact rat model, which mimics the human situation of reperfused myocardial infarction, could be highly valuable for the testing of new drugs to treat reperfusion injury, thereby facilitating translational research.