Advanced Imaging Techniques for Cardiovascular Research

Abstract

Objectives: In this thesis we addressed some of those difficulties by exploring new applications of a 68Galabeled radiotracer (68Ga-DOTA). 68Ga can be obtained from a 68Ge/68Ga generator and has a half-life of 68 minutes, which makes it a convenient candidate for its widespread clinical use. We proposed and validated the use of 68Ga-DOTA as a radiotracer for assessment of myocardial blood flow (MBF), myocardial viability and pulmonary blood flow (PBF). Additionally, we introduced a new methodology to perform a PET scan in which this tracer could be coinjected simultaneously with some other radiotracers such as 18FDG (multi-tracer PET). Lastly, we developed an automatic detector able to perform blood spectroscopy analysis, which offered the possibility to perform multi-tracer PET with minimal human intervention. Methods To test the capability of 68Ga-DOTA to measure MBF, viability and PBF, different groups of Large White pigs underwent PET/CT scans using 68Ga-DOTA as the injected radiotracer. For PBF studies, a group of healthy pigs (n = 4) were scanned under rest conditions. For MBF studies, a group of 8 pigs were scanned under rest and pharmacologically-induced stress in order to perform rest/stress tests, as it is done for humans in clinical routine. Additionally, a group of 5 pigs were scanned 7 days after the induction of a myocardial infarction (MI) to assess viability and MBF in a MI model. MBF, extracellular volume fraction (ECV, for viability assessment) and PBF maps were obtained after fitting the dynamic PET images to the corresponding pharmacokinetic model followed by 68Ga-DOTA in each tissue under study. Global and regional perfusion maps for the myocardial tissue (MBF) and lungs (PBF) were obtained. For validation purposes, the “goldstandard” technique used in tissue perfusion quantification (fluorescent-labeled microspheres (MS)) was simultaneosly performed along with the PET/CT scans. The blood sampling spectroscopic methodology was evaluated and calibrated in vitro using different 68Ga/18F mixtures. Then, it was tested in pigs (n = 3) injected with 68Ga-DOTA and 18FDG in the same acquisition. The activity concentration of each radiotracer in myocardial tissue was subsequently measured ex vivo. The automatic blood sampling detector was built from scratch and characterized using a catheter filled with different 68Ga/18F mixtures. Finally, it was additionally evaluated in vivo in n = 3 pigs under conditions resembling to those encountered in clinical routine. Results Regarding MBF quantification and validation with 68Ga-DOTA-PET, a strong correlation (r = 0.91) between MBF measured with PET and MS was obtained (slope = 0.96 ± 0.10, y-intercept = 0.11 ± 0.19 ml·min−1·g−1). For the myocardial infarction model, MBF values obtained with 68Ga-DOTA-PET in the infarcted area (LAD, left anterior descendant) were significantly reduced in comparison to remote ones LCX (left circumflex artery, p < 0.0001) and RCA (right coronary artery, p < 0.0001). In addition, 68Ga-DOTA-PET detected a significant ECV increase in the infarcted area (p < 0.0001). The correlation evaluation between 68Ga-DOTA-PET and MS as a PBF radiotracer also showed a good and significant correlation (r = 0.74, p < 0.0001). The gamma spectroscopic analysis on blood samples proposed for multi-tracer PET imaging was also succesfully validated, showing a correlation of r = 0.95 (p < 0.0001) for 18FDG concentration in myocardium measured with multi-tracer PET and by ex vivo validation. The blood sampling detector was able to measure the arterial input function in pigs in an experimental setup under realistic conditions. Discussion and conclusions 68Ga-DOTA-PET allowed accurate non-invasive assessment of MBF and ECV in pigs with myocardial infarction and under rest-stress conditions. This technique could provide wide access to quantitative measurement of both MBF and ECV with PET imaging. 68Ga-DOTA-PET was also demonstrated to be a potential inexpensive method for measuring PBF in clinical settings. As for multi-tracer PET imaging, the proposed methodology allowed explicit measurement of separate arterial input functions, offering very similar results to those obtained as a reference from the ex vivo analysis of the tissue under evaluation. Finally, a novel blood sampling device was developed and characterized, showing performance parameters similar to other devices in the literature. Noteworthy, this detector has the additional and unique feature of allowing us to perform multi-tracer PET by means of a gamma spectroscopic analysis of the blood flowing between its detection blocks. All the results summarized in this abstract may contribute to spread the use of PET in clinical routine, either by the clinical use of 68Ga-DOTA as an inexpensive but accurate radiotracer for MBF, PBF or viability assessment, or by the implementation of multi-tracer PET, which could lead to cost reduction of PET examinations by shortening the scanning time and eliminating misalignment inaccuracies. This multi-tracer PET methodology could also be safely implemented using our proposed automated device that permits to perform the gamma spectroscopic analysis on blood samples with minimal human intervention.