Abstract
Angiogenesis plays a central role in the healing process following acute myocardial infarction. The PET tracer [68Ga]-NODAGA-RGD, which is a ligand for the αvβ3 integrin, has been investigated for imaging angiogenesis in the process of healing myocardium in both animal and clinical studies. It’s value as a prognostic marker of functional outcome remains unclear. Therefore, the aim of this work was to establish [68Ga]-NODAGA-RGD for imaging angiogenesis in the murine infarct model and evaluate the tracer as a predictor for cardiac remodeling in the context of cardiac stem cell therapy. [68Ga]-NODAGA-RGD PET performed seven days after left anterior descending coronary artery (LAD) occlusion in 129S6 mice showed intense tracer accumulation within the infarct region. The specificity was shown in a sub-group of animals by application of the competitive inhibitor cilengitide prior to tracer injection in a subgroup of animals. Myocardial infarction (MI) significantly reduced cardiac function and resulted in pronounced left ventricular remodeling after three weeks, as measured by cardiac MRI in a separate group. Cardiac induced cells (CiC) that were derived from mESC injected intramyocardially in the therapy group significantly improved left ventricular ejection fraction (LVEF). Surprisingly, CiC transplantation resulted in significantly lower tracer accumulation seven days after MI induction. Accordingly, we successfully established the PET tracer [68Ga]-NODAGA-RGD for the assessment of αvβ3 integrin expression in the healing process after MI in the mouse model. Yet, our results indicate that the mere extent of angiogenesis following MI does not serve as a sufficient prognostic marker for functional outcome.
Highlights
Acute myocardial infarction (MI) is a leading cause of death in most developed countries and is mostly induced by the occlusion of a coronary artery
The expression of αv β3 -integrin has been shown in both rats and pigs to be an appropriate surrogate marker for imaging angiogenesis during the healing process of myocardial infarction [10,12]
We injected the competitive inhibitor cilengitide 10 min. prior to the application of the tracer in a subgroup of three animals, which suppressed the uptake of [68 Ga]-NODAGA-RGD to the level the SHAM group in order to assess the specificity of the tracer (0.79 ± 0.14% ID/g vs. 0.72 ± 0.24% ID/g; p = 0.71) (Figure 3D)
Summary
Acute myocardial infarction (MI) is a leading cause of death in most developed countries and is mostly induced by the occlusion of a coronary artery. Myocardial healing following the ischemic event is a highly dynamic and complex process, which can be divided into three distinct phases [2]. The early inflammatory phase is dominated by infiltrating leucocytes scavenging the wound of necrotic tissue. Fibroblasts differentiate into myofibroblasts and deposit a provisional extracellular matrix, which is rich in fibrin and fibronectin. This proliferative phase is highly energy demanding and it depends on effective angiogenesis, a process that is defined as sprouting of pre-existing post-capillary venules into the provisional extracellular matrix. Myofibroblasts undergo apoptosis, microvessels regress, and a collagen-rich mature scar replaces the metabolically active immature scar [2]
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