Abstract
Cellular inflammation following acute myocardial infarction has gained increasing importance as a target mechanism for therapeutic approaches. We sought to investigate the effect of syngeneic cardiac induced cells (CiC) on myocardial inflammation using 18F-FDG PET (Positron emission tomography)-based imaging and the resulting effect on cardiac pump function using cardiac magnetic resonance (CMR) imaging in a mouse model of myocardial infarction. Mice underwent permanent left anterior descending coronary artery (LAD) ligation inducing an acute inflammatory response. The therapy group received an intramyocardial injection of 106 CiC into the border zone of the infarction. Five days after myocardial infarction, 18F-FDG PET was performed under anaesthesia with ketamine and xylazine (KX) to image the inflammatory response in the heart. Flow cytometry of the mononuclear cells in the heart was performed to analyze the inflammatory response. The effect of CiC therapy on cardiac function was determined after three weeks by CMR. The 18F-FDG PET imaging of the heart five days after myocardial infarction (MI) revealed high focal tracer accumulation in the border zone of the infarcted myocardium, whereas no difference was observed in the tracer uptake between infarct and remote myocardium. The CiC transplantation induced a shift in 18F-FDG uptake pattern, leading to significantly higher 18F-FDG uptake in the whole heart, as well as the remote area of the heart. Correspondingly, high numbers of CD11+ cells could be measured by flow cytometry in this region. The CiC transplantation significantly improved the left ventricular ejection function (LVEF) three weeks after myocardial infarction. The CiC transplantation after myocardial infarction leads to an improvement in pump function through modulation of the cellular inflammatory response five days after myocardial infarction. By combining CiC transplantation and the cardiac glucose uptake suppression protocol with KX in a mouse model, we show for the first time, that imaging of cellular inflammation after myocardial infarction using 18F-FDG PET can be used as an early prognostic tool for assessing the efficacy of cardiac stem cell therapies.
Highlights
Inflammatory activity of the innate immune system following myocardial infarction substantially influences remodeling after myocardial infarction (MI) and the evolution of heart failure [1]
In order to ascertain the differentiation status of the cells, we examined the expression of various markers at the beginning and at day six of differentiation (Figure 3A)
Translational cardiovascular research has evolved at an incredible pace within the last decade and resulted in significantly higher survival rates after acute myocardial infarction
Summary
Inflammatory activity of the innate immune system following myocardial infarction substantially influences remodeling after myocardial infarction (MI) and the evolution of heart failure [1]. The balance of pro- and anti-inflammatory immune cells and their recruiting mechanisms are discussed as both therapeutic and prognostic targets [1]. Further understanding of this intricate cellular immune response to myocardial ischemia in a translational setting requires non-invasive molecular imaging tools. The 18F-FDG PET (Positron emission tomography) using specific protocols for suppressing glucose uptake in cardiomyocytes has recently been introduced to detect cellular inflammation following MI in both patients and C57BL/6 mice [1,3,4,5]
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