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 ¹⁸F-labeled 2-(5-fluoropentyl)-2-methyl-malonic acid (¹⁸F-ML-10) and ¹⁸F-labeled 2-(3-fluoropropyl)-2-methyl-malonic acid (¹⁸F-ML-8) for apoptosis imaging in rat models of myocardial infarction (MI) and compared them with ¹⁸F-fluorodeoxyglucose (¹⁸F-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 ¹⁸F-FDG. In vivo PET imaging with ¹⁸F-ML-10 and ¹⁸F-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 validate ¹⁸F-ML-8 binding to apoptotic cardiomyocytes. PET imaging demonstrated high ¹⁸F-ML-10 and ¹⁸F-ML-8 uptake where ¹⁸F-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 for ¹⁸F-ML-10 and 3.51 ± 0.18 for ¹⁸F-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 ¹⁸F-ML-8 uptake than with ¹⁸F-ML-10 uptake. Ex vivo cell binding assays demonstrated that ¹⁸F-ML-8 accumulated in apoptotic cells but not in necrotic or normal cells. PET imaging using ¹⁸F-ML-10 or ¹⁸F-ML-8 allows the noninvasive detection of myocardial apoptosis in the early phase. In addition, ¹⁸F-ML-8 may be better than ¹⁸F-ML-10 for apoptosis imaging. We propose that PET imaging with ¹⁸F-ML-10 or ¹⁸F-ML-8 combined with ¹⁸F-FDG is an alternative for detecting and assessing MI.

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