Functional cardiac imaging in mice using Ta–178

Abstract

Recent advances in genetic manipulations affecting the cardiovascular system in mice 1,2 have produced promising new tools for studying cardiac pathophysiology and have in turn created a need for high-quality imaging in very small animals. For example, in assessing adaptations of genetically altered mice to pressure overload 3 or coronary occlusion simulating human heart diseases 4-6 , it is often necessary to quantify ventricular function in vivo several times before and during adaptation. Ultrasound 7-9 , X-rays 10 , and magnetic resonance imaging 11 (MRI) are among the methods that are being adapted for use in mice, but these techniques all have marginal spatial and temporal resolution for use in animals weighing less than 30 g and with heart rates exceeding 600 beats/min. Radionuclide ventriculographyWe have adapted a form of radionuclide ventriculography used to quantify right ventricular (RV) and left ventricular (LV) ejection fraction (EF) in man for use in mice [12][13][14] . In this method, blood is imaged by detecting the radioactivity of a tracer injected as a bolus into a vein and followed during its passage through the heart. For murine imaging, a multiwire gamma camera 13 optimized for use with Ta-178 was fitted with a pinhole lens 2 mm in diameter positioned 15 cm from the image plane. This was done to project an enlarged image of the mouse heart on the humansized 32 × 32 pixel array at a frame rate of 160/s, compared with 40/s for human imaging (Fig. 1). The Ta-178 (half-life of 9.3 min) is generated and concentrated on site as needed from W-178 (half-life of 21.7 days) 15 using a semi-automated system to maximize consistency. The short half-life allows concentration of human-size doses (20 mCi) in mouse-size volumes (20 µl) to compensate for the 1/2,500 smaller heart volume and 1/4 shorter image acquisition time with acceptable radiation exposure. Murine imagingTo provide a wide range of ejection fractions, evaluations were done in 18 normal mice, 13 sham-operated mice, and 44 mice with myocardial infarctions produced by left anterior descending (LAD) coronary artery occlusions 6 . We made multiple measurements of LVEF in each animal with either no intervention, a positive inotrope (dobutamine), or a negative inotrope (verapamil) to assess repeatability and the response to agents with known effects on EF in larger animals. Before imaging, mice were anesthetized with 0.2-0.4 ml of pentobarbital sodium solution (4 mg/ml) given intraperitoneally and were taped supine to a small plastic board with ECG electrodes under each limb (Fig. 1a). A jugular line (PE-10 tubing) was placed for injection of 20 mCi of Ta-178 as a bolus in 10 µl of 0.1 molar HCl followed by 10 µl of normal saline. After injection, images were taken for 7.5 s at 160 frames/s and were stored and analyzed by software originally designed and validated 13 for human cardiac imaging and assessment of EF. End-diastolic images from consecutive cardiac cycles after injection are shown in Fig. 2a, along with a scaled photo of a mouse heart. ...

Use of echocardiography for the phenotypic assessment of genetically altered mice

“…Magnetic resonance imaging and ultrafast CT scanning offer accurate estimation of LV mass (10,32), but their use may be limited by expense and availability. Contrast-enhanced X-ray ventriculography and radionuclide techniques for the assessment of mouse cardiovascular function have also been adapted for studies in mice (14,30). Although three-dimensional echocardiography (34) and transesophageal imaging (33) of the murine heart is feasible and may offer a theoretical potential for assessing hearts of widely varying sizes, these techniques are technically challenging for broad application to a variety of murine models or are limited by low frame rates.…”

Towards in vivo nuclear microscopy: iodine-125 imaging in mice using micro-pinholes

“…1, we see that an image resolution approaching the pinhole diameter can be obtained when the pinhole to detector distance is sufficiently large and the object is close to the pinhole. The smallest pinhole diameters reported so far are about 0.5 mm, and have resulted in a SPET image resolution of about 1 mm [6,7,8].…”

“…1) offers the ability to obtain high-resolution images of gamma-emitting tracers in small objects like the human thyroid and small animals [6,7,8]. However, a fundamental factor limiting image resolution is the penetration of gammaradiation along the edge of the pinhole collimator.…”

Noninvasive Cardiovascular Phenotyping in Mice

“…Thus, resting values for these and other parameters may be nearly normal, and interventions must be performed to reveal phenotypic differences in the response to stress. Interventions can include inotropic Hartley et al 1995Hartley et al , 1999, chronotropic, and vasoactive (Banda et al 1997;Hartley et al 1997) pharmaceuticals, exercise (Desai et al 1997;Spencer et al 2000), and/or surgical manipulations such as coronary occlusion (Briaud et al 2001;Jones et al 1999;Kurrelmeyer et al 2000;Michael et al 1995Michael et al , 1999Patten et al 1998;Verdouw et al 1998) or aortic constriction (Hongo et al 1997;Rockman et al 1993;Zhang et al 2000). The ability to perform serial noninvasive studies and to measure the responses to interventions is powerful because the animal can be used as its own control, and it is not necessary to assess or assume so-called normal values.…”