Our laboratory pioneered the application of cardiac imaging techniques in mouse models of T. cruzi
-induced heart disease. 11,13,27
In previous studies, we showed the use of cardiac MRI and echocardiography in the evaluation of alterations in structure and function accompanying this infection. MicroPET is a relatively new technique for evaluating cardiac structure and function. 28
In this study using this technique, we showed for the first time that T. cruzi
-infected mice display greater uptake of glucose throughout the time course of infection compared with uninfected controls. Importantly, this is the first study comparing data from three different noninvasive imaging modalities, MRI, echocardiography, and micro-PET, for the serial assessment of myocardial viability and cardiac structure and function in mice infected with T. cruzi
from acute to chronic phase.
Cardiac MRI findings confirmed our previous observation of significant dilatation of the right ventricular chamber was from 30 to 100 dpi in infected mice when compared with controls. 10,13,27,29,30
There was no difference in the left ventricular internal diameter between groups and LVWT was increased only at 100 dpi. MRI allows accurate, high resolution 3D characterization of cardiac structure within a single examination and allows the quantification of volumetric changes in hearts. 31
However, technical difficulties related to anesthesia, irregular heart rates, and thermoregulation can arise during the acquisition of cardiac gated MRI studies, which require signal averaging over a time period of several minutes. 32,33
Echocardiography confirmed our previous observation that the ejection fraction, a measurement of myocardial systolic performance, was decreased at 60 and 100 dpi. 11
Echocardiography has been used by our group. 11,34,35
and others 36–40
as an important tool in the assessment of cardiac function in murine models of cardiac disease. A particular disadvantage of the echocardiographic method for evaluation of hearts of T. cruzi
-infected mice is the difficulty in assessing the RV, because the images are typically acquired along the parasternal long axis, which obscures the location of the RV.
Our MicroPET study showed that T. cruzi
-infected mice displayed increased uptake of glucose in the myocardium when compared with controls as early as 15 dpi, whereas alterations in morphologic parameters, such as right ventricular internal diameter (RVID) and LVWT, were not detected by MRI until 30 dpi. Alteration in cardiac function measured by echocardiography (ejection fraction) was not detected until 60 dpi. The PET uptake provides information regarding the metabolic state of the myocardium through the regional uptake of 18
F-FDG, a glucose analogue. 41
After transport into cells, 18
F-FDG undergoes subsequent hexokinase-mediated phosphorylation, but is not further metabolized resulting in metabolic trapping of the radiotracer in cells that exhibit enhanced glucose metabolism. 14
MicroPET has been used for monitoring metabolic events in the myocardium of small animals in stem cell transplantation after myocardial infarction, 41,42
progressive hypertrophy, 43
and left ventricular dilation. 44
Increased FDG uptake has been shown in vitro
in leukocytes, 45
lymphocytes, and macrophages 46,47
and in vivo
in acute myocardial infarction, 48
abdominal aortic aneurism, 49
and atherosclerosis. 50
The increased uptake of FDG in T. cruzi
-infected mice correlates with the intense and diffuse myocarditis observed during the acute phase and chronic inflammation and myocardium reparative fibrosis that occurs during the chronic phase. An important characteristic of PET is that it is largely independent of the thickness of the object and the depth of the source within the subject. Thus, in addition to providing information on glucose uptake, the microPET images also permit visualization of the dilation of the RV (as shown in ) and contractility (see Supplemental data).
In conclusion, we showed that by combining complementary imaging methodologies, MRI, echocardiography, and MicroPET it is possible to noninvasively quantify parameters related to cardiovascular function, morphology, and myocardium metabolism of mice infected with T. cruzi from the earliest days of infection through the chronic phase. Our MicroPET data shows metabolic changes in the LV as early as 15 dpi, likely associated with inflammation that appears before alterations in structure and function of the myocardium are detected. These approaches permit serial examinations and can be used in longitudinal studies over the time course of the disease process to provide important insights into disease biology and pathophysiology. Furthermore, these findings suggest that PET may be a useful tool to track early response to therapeutic agents and to evaluate efficacy of therapeutics in patients.