Detection of cardiac apoptosis by [18F]ML-10 in a mouse model of permanent LAD ligation

Abstract

Purpose: The loss of viable cardiac cells and cell death by myocardial infarction (MI) is still a significant obstacle in preventing deteriorating heart failure. Imaging of apoptosis, a defined cascade to cell death, could identify areas at risk.

Procedures: Using 2-(5-[¹⁸F]fluoropentyl)-2-methyl-malonic acid ([¹⁸F]ML-10) in autoradiography and positron emission tomography (PET) visualized apoptosis in murine hearts after permanent ligation of the left anterior descending artery (LAD) inducing myocardial infarction (MI). 2-deoxy-2-[¹⁸F]fluoro-D-glucose ([¹⁸F]FDG) PET imaging localized the infarct area after MI. Histology by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) staining validated apoptosis in the heart.

Results: Accumulation of [¹⁸F]ML-10 was evident in the infarct area after permanent ligation of the LAD in autoradiography and PET imaging. Detection of apoptosis by [¹⁸F]ML-10 is in line with the defect visualized by [¹⁸F]FDG and the histological approach.

Conclusion: [¹⁸F]ML-10 could be a suitable tracer for apoptosis imaging in a mouse model of permanent LAD ligation.

Keywords: Apoptosis; Autoradiography; Cardiac positron emission tomography; Myocardial infarct; [18F]FDG; [18F]ML-10.

Fig. 1

Autoradiography of [¹⁸F]ML-10 after MI (A) Structure of [¹⁸F]ML-10. (B) Schematic study design illustrating the induction of myocardial infarct (MI) by permanent LAD ligation, injection of [¹⁸F]ML-10 and [¹⁸F]FDG, autoradiography, PET imaging, and histology at different time points. (C) Autoradiographic evaluation of the [¹⁸F]ML-10 uptake after MI at different time points. Hearts are illustrated at different sections (apex, mid-ventricular, base). (D) Quantification of the target-to-background ratio (TBR) after different time points. N = 2–3. Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001

Fig. 2

[¹⁸F]FDG and [¹⁸F]ML-10 PET imaging after MI. (A) Representative [¹⁸F]FDG image illustrating the MI. Arrows indicate the infarct area of the left ventricle. R right, L left, D dorsal, V ventral. Color scale: Volcano. (B) Representative images of [¹⁸F]FDG and [¹⁸F]ML-10 after permanent LAD ligation. Arrows indicate infarct area detected by diminished [¹⁸F]FDG uptake and evident [¹⁸F]ML-10 uptake. Color scale: Ocean. (C) Quantification of the injected dose per gram of [¹⁸F]ML-10 after different time points. N = 5–7. Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001

Fig. 3

Histological evaluation by TUNEL staining after MI. (A) TUNEL staining of the heart after MI. Right ventricular myocardium (RVM), interventricular septum (IVS), left ventricle LV, left ventricular myocardium (LVM). Bar equals 500 μm. (B) Quantification of TUNEL positive cells in the whole heart after different time points. N = 5–7. (C) Quantification of TUNEL positive cells in the infarct area after different time points. N = 5–7. (D) Quantification of TUNEL positive cells in the remote area after different time points. N = 5–7. Data represent mean ± SEM. * p < 0.05, ** p < 0.01, *** p < 0.001