PET imaging of cardiomyocyte apoptosis in a rat myocardial infarction model

Abstract

Cardiomyocyte apoptosis has been observed in several cardiovascular diseases and contributes to the subsequent cardiac remodeling processes and progression to heart failure. Consequently, apoptosis imaging is helpful for noninvasively detecting the disease progression and providing treatment guidance. Here, we tested F-labeled 2-(5-fluoropentyl)-2-methyl-malonic acid (F-ML-10) and F-labeled 2-(3-fluoropropyl)-2-methyl-malonic acid (F-ML-8) for apoptosis imaging in rat models of myocardial infarction (MI) and compared them with F-fluorodeoxyglucose (F-FDG). MI was induced in Sprague-Dawley rats by permanent left coronary artery ligation. Procedural success was confirmed by echocardiography and positron emission tomography (PET) imaging with F-FDG. In vivo PET imaging withF-ML-10 and F-ML-8 was performed in the MI models at different time points after operation. Terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assays and immunohistochemical analyses were used to evaluate myocardial apoptosis. In vitro cell binding assays were performed to validateF-ML-8 binding to apoptotic cardiomyocytes. PET imaging demonstrated high F-ML-10 andF-ML-8 uptake where F-FDG uptake was absent. The focal accumulation of the two tracers was high on days 1 and 3 but was not notable on days 5 and 7 after surgery. The infarct-to-lung uptake ratio was 4.29 ± 0.30 forF-ML-10 and 3.51 ± 0.18 for F-ML-8 (n = 6, analyzed by averaging the uptake ratios on postoperative days 1 and 3, P< 0.05). The TUNEL results showed that myocardial cell apoptosis was closely related to the focal uptake of the apoptotic tracers in the infarct area. In addition, the apoptosis rates calculated from the TUNEL results were better correlated with F-ML-8 uptake than withF-ML-10 uptake. Ex vivo cell binding assays demonstrated that F-ML-8 accumulated in apoptotic cells but not in necrotic or normal cells. PET imaging usingF-ML-10 or F-ML-8 allows the noninvasive detection of myocardial apoptosis in the early phase. In addition,F-ML-8 may be better than F-ML-10 for apoptosis imaging. We propose that PET imaging withF-ML-10 or F-ML-8 combined withF-FDG is an alternative for detecting and assessing MI.

Crosstalk between Circulatory Microenvironment and Vascular Endothelial Cells in Acute Myocardial Infarction

“…18 Cardiomyocyte apoptosis was observed in some cardiovascular diseases including AMI. 48 After AMI, the pathway of abnormal expression will be further discussed. PI3K Akt signaling pathway, apoptosis and platelets activation are enriched in platelets, endothelial cells and mononuclear cells respectively.…”

Radionuclide imaging of apoptosis for clinical application

“…It shared the same dynamic uptake process with 18 F-ML-10 and both can differentiate apoptosis from necrosis. Moreover, according to a study performed by Hui Ma and colleagues [28], in a rat myocardial infarction model, 18 F-ML-8 activity showed better correlation with apoptosis rates calculated from the TUNEL test than 18 F-ML-10 uptake. Although requiring more evidences and clinical attempts, 18 F-ML-8 may be potentially more suitable for clinical evaluation of apoptosis and deemed more feasible for translation.…”

18F-Trifluoromethylated D-Cysteine as a Promising New PET Tracer for Glioma Imaging: Comparative Analysis With MRI and Histopathology in Orthotopic C6 Models

“…Then, they were cut into continuous 3-μm slices. Several stainings were further performed, and the methods were reported previously ( 22 – 24 ). The HE staining was performed to validate the tumor morphology and delineate the tumor boundary.…”

“…Immunohistochemical staining for Ki67 (monoclonal antibody, Servicebio, Wuhan, China, GB13030-2) was performed using the Envision method ( 22 ), and the Ki67 index represents the proliferative activity of glioma cells. The tumor sections were reviewed and quantified based on the percentage of positive cells in the highest density staining area; all cells with nuclear staining of any intensity were considered positive, and the Ki67 values were defined as the percentage of positive cells among the total cells counted ( 24 ).…”