Rabbit models: ideal for imaging purposes?

In translational medical research, experimental animal models play a prominent role in elucidating physiological and pathophysiological mechanisms involved in human disease. As to cardiac function, the technique to perfuse the isolated heart in vitro has had tremendous impact for more than 100 years [1]. With regard to acute, subacute, and chronic myocardial infarction, animal models predominantly employed large animals like dogs and pigs. More recently also rabbits, rats and mice were employed, as these models benefit from low costs, large numbers of experiments, and ease of housing the animals during the experiment. An additional advantage of the use of small animals is the lower risk of ventricular fibrillation after coronary occlusion and reperfusion in small animals rather than in large animals, leading to less drop outs from the experiment. A large disadvantage of the use of small animals is the lack of dedicated imaging instruments, such as multi-slice computed tomography (MSCT) [2‐13], radionuclide imaging and positron emitting tomography (PET) [14‐20] and magnetic resonance imaging (MRI) [21‐33], which are successfully being used in humans.

At present these advanced imaging modalities can also be applied in myocardial infarction studies in small animals. For example, in a study on cardiac function of ischemic hearts before and after intramyocardially administered mesenchymal stem cells in mice in vivo, Grauss et al. [34, 35] used a 9.4 Tesla MR apparatus with a vertical bore (diameter 89 mm) normally used for characterization of chemical compounds. Although MR images had high quality, the use of these apparatus for ischemic heart research in small experimental animals is very complicated and only successful after long and intensive training.

The present paper by Feng et al. [36] presents an animal model of myocardial ischemia and reperfusion in rabbits studied in a clinical 1.5 Tesla MRI scanner. In anesthetised rabbits on artificial respiration the thorax was opened, the left circumflex coronary artery branch was ligated by a suture with a slip knot, and reperfused 90 min later by pulling the suture in the closed-chest condition. After injection of 0.3 mmol/kg of gadolinium-DTPA, myocardial area and myocardial volume showing delayed contrast enhancement were quantified. These data was correlated to the classical histochemical data of infarcted area and volumes, and found to correlate well. The authors were also able to quantify end-systolic and end-diastolic volumes, to calculate stroke volume and ejection fraction. Thus, using a clinical MRI scanner, the normal and post-infarct reperfused rabbit heart in vivo can be studied for left ventricular function and infarct size. This research group has a track record in developing novel contrast agents for MRI purposes, particularly porphyrin and nonporphyrin necrosis-avid contrast agents (NACAs). It was shown that this rabbit model with reperfused myocardial infarction allows the study of a novel infarct-avid tracer using a clinical MRI scanner. The choice of rabbits is an excellent one for several reasons: (1) the heart rate of anesthetised rabbits is not beyond the range of human heart rates, implying that ECG-triggering does not lead to major problems, (2) the rabbit myocardium has a positive force-frequency relation, (3) rabbits are relatively inexpensive, (4) an entire transverse section of the heart can be placed and observed on a standard microscope glass slide, and (5) there are rabbit strains with heritable hyperlipidemia, such as the Watanabe strain, allowing studies in hearts with coronary atherosclerosis. As also mentioned by the authors, image quality can be improved further by optimizing the “human” cMRI sequences for the rabbit heart.

The present study clearly demonstrates that a not-too-small experimental animal, the rabbit, can be usefully studied in a clinical MRI scanner, thereby contributing to cost-effectiveness of animal studies. The acquired images are outstanding and provide results that correlated well with histochemical analyses, thereby contributing to the accuracy. As a result, rabbit models are very suitable for imaging purposes. When further optimizing imaging quality, they might become ideal.