Inhibition of Interleukin-6 Receptor in a Murine Model of Myocardial Ischemia-Reperfusion.

BACKGROUND: Interleukin-6 (IL-6) levels are upregulated in myocardial infarction. Recent data suggest a causal role of the IL-6 receptor (IL-6R) in coronary heart disease. We evaluated if IL-6R blockade by a monoclonal antibody (MR16-1) prevents the heart from adverse left ventricular remodeling in a mouse model of ischemia-reperfusion (I/R). METHODS: CJ57/BL6 mice underwent I/R injury (left coronary artery ligation for 45 minutes) or sham surgery, and thereafter received MR16-1 (2mg/mouse) 5 minutes before reperfusion and 0.5mg/mouse weekly during four weeks, or control IgG treatment. Cardiac Magnetic Resonance Imaging (CMR) and hemodynamic measurements were performed to determine cardiac function after four weeks. RESULTS: I/R caused left ventricular dilatation and a decrease in left ventricular ejection fraction (LVEF). However, LVEF was significantly lower in the MR16-1 treatment group compared to the IgG group (28±4% vs. 35±6%, p = 0.02; sham 45±6% vs. 43±4%, respectively; p = NS). Cardiac relaxation (assessed by dP/dT) was not significantly different between the MR16-1 and IgG groups. Also, no differences were observed in histological myocardial fibrosis, infarct size and myocyte hypertrophy between the groups. CONCLUSION: Blockade of the IL-6R receptor by the monoclonal MR16-1 antibody for four weeks started directly after I/R injury did not prevent the process of cardiac remodeling in mice, but rather associated with a deterioration in the process of adverse cardiac remodeling.

Evaluation of infarcted murine heart function: comparison of prospectively triggered with self-gated MRI.

Measurement of cardiac function is often performed in mice after, for example, a myocardial infarction. Cardiac MRI is often used because it is noninvasive and provides high temporal and spatial resolution for the left and right ventricle. In animal cardiac MRI, the quality of the required electrocardiogram signal is variable and sometimes deteriorates over time, especially with infarcted hearts or cardiac hypertrophy. Therefore, we compared the self-gated IntraGateFLASH method with a prospectively triggered FLASH (fast low-angle shot) method in mice with myocardial infarcts (n = 16) and in control mice (n = 21). Mice with a myocardial infarct and control mice were imaged in a vertical 9.4-T MR system. Images of contiguous 1-mm slices were acquired from apex to base with prospective and self-gated methods. Data were processed to calculate cardiac function parameters for the left and right ventricle. The signal-to-noise and contrast-to-noise ratios were calculated in mid-ventricular slices. The signal-to-noise and contrast-to-noise ratios of the self-gated data were higher than those of the prospectively gated data. Differences between the two gating methods in the cardiac function parameters for both left and right ventricle (e.g. end-diastolic volumes) did not exceed the inter-observer variability in control or myocardial infarcted mice. Both methods gave comparable results with regard to the cardiac function parameters in both healthy control mice and mice with myocardial infarcts. Moreover, the self-gated method provided better signal-to-noise and contrast-to-noise ratios when the acquisition time was equal. In conclusion, the self-gated method is suitable for routine use in cardiac MRI in mice with myocardial infarcts as well as in control mice, and obviates the need for electrocardiogram triggering and respiratory gating. In both gating methods, more than 10 frames per cardiac cycle are recommended.

Negative MR contrast caused by USPIO uptake in lymph nodes may lead to false positive observations with in vivo visualization of murine atherosclerotic plaque.

OBJECTIVE: USPIOs are used clinically as contrast agent for magnetic resonance imaging (MRI) of lymph nodes, and in research settings for MRI of macrophages in atherosclerotic lesions. However, T2* weighted (T2*w) imaging can lead to "blooming" with overestimation of the area occupied by USPIOs. In this study, plaque uptake of USPIOs in atherosclerotic mice was investigated in the presence and absence of circulating monocytes. The influence of peri-aortic lymph node uptake on the interpretation of T2*w images of the aortic wall was studied. METHODS: Atherosclerotic mice were fed an atherogenic diet and were randomized to total body irradiation or non-irradiation. After 2 days, T2*w MRI of the abdominal aorta was performed, followed by intravenous administration of 100mumol/kg USPIOs (t=0). At t=3 and 5 days MRI of the abdominal aorta was repeated. Animals were sacrificed and histological evidence for iron uptake by aortic wall and lymph nodes was compared with the degree of focal signal loss on in vivo MR images. RESULTS: Aortic walls in irradiated and non-irradiated mice, but also in healthy wild-type mice, showed signal loss on T2*w MRI. Signal loss however did not correspond with histological evidence of USPIO uptake by aortic wall but by peri-aortic lymph nodes. CONCLUSIONS: The versatility of USPIOs as a negative MR contrast agent for both lymph node staging and atherosclerosis may limit the use for detection of atherosclerotic lesions in vessels where lymph nodes are highly prevalent.