In Vivo Monitoring of Parathyroid Hormone Treatment after Myocardial Infarction in Mice with [68Ga]Annexin A5 and [18F]Fluorodeoxyglucose Positron Emission Tomography
[68Ga]Annexin A5 positron emission tomography (PET) reveals the externalization of phosphatidylserine as a surrogate marker for apoptosis. We tested this technique for therapy monitoring in a murine model of myocardial infarction (MI) including parathyroid hormone (PTH) treatment. MI was induced in mice, and they were assigned to the saline or the PTH group. On day 2, they received [68Ga]annexin A5 PET or histofluorescence TUNEL staining. Mice had 2-deoxy-2-[18F]fluoro-D-glucose (FDG)-PET examinations on days 6 and 30 for calculation of the left ventricular ejection fraction and infarct area. [68Ga]Annexin A5 uptake was 7.4 ± 1.3 %ID/g within the infarction for the controls and 4.5 ± 1.9 %ID/g for the PTH group (p = .013). TUNEL staining revealed significantly more apoptotic cells in the infarct area on day 2 in the controls (64 ± 9%) compared to the treatment group (52 ± 4%; p = .045). FDG-PET revealed a significant decrease in infarct size in the treatment group and an increase in the controls. Examinations of left ventricular ejection fraction on days 6 and 30 did not reveal treatment effects. [68Ga]Annexin A5 PET can detect the effects of PTH treatment as a marker of apoptosis 2 days after MI; ex vivo examination confirmed significant rescue of myocardiocytes. FDG-PET showed a small but significant reduction in infarct size but no functional improvement.
ANIMAL STUDIES have suggested that parathyroid hormone (PTH) treatment after myocardial infarction (MI) shows beneficial effects on infarct size, left ventricular function, and cardiac remodeling and in general attenuates the progression of ischemic cardiomyopathy.1,2 Several mechanisms potentially mediating these effects of PTH have been proposed. First, PTH is known to induce arterial vasodilation by means of a receptor activation evoking intracellular cyclic adenosine monophosphate (cAMP) production.1,2 This pathway plausibly exerts beneficial effects on the perfusion of ischemically afflicted myocardium. Second, PTH induces the mobilization of progenitor cells from the bone marrow into the peripheral blood.3 Third, PTH increases plasma levels of cardiac stromal cell–derived factor 1 (SDF-1), a chemokine facilitating the homing of stem cells into the ischemic heart by activation of chemokine receptor type 4 (CXCR4) (SDF-1/CXCR4 axis).4 These effects lead to increased myocardial perfusion, neovascularization, and enhanced cell survival and regeneration, ultimately resulting in less apoptosis and cardiac remodeling and improved postinfarct cardiac function.1
Serial examinations by positron emission tomography (PET) enable serial in vivo molecular imaging of myocardial survival and viability in small-animal infarct models. PET with the glucose analogue 2-deoxy-2-[18F]fluoro-D-glucose (FDG-PET) gives quantitative information about the viability and the function of damaged myocardium in vivo.5 Furthermore, we recently reported that PET with [68Ga]annexin A5 serves to visualize and quantify phosphatidylserine externalization in the area at risk after myocardial ischemia6; the binding of [68Ga]annexin A5 to externalized phospholipids is considered a surrogate marker for myocardial apoptosis.
Based on our earlier findings with FDG and annexin PET, we hypothesized that the myocardial viability and externalization of phosphatidylserine on day 2 after MI correlate with the long-term outcome
