Abstract
Cardiac healing after myocardial ischemia is a complex biological process. Advances in understanding of wound healing response have paved the way for clinical testing of novel molecular imaging to improve clinical outcomes. A key factor for assessing myocardial viability after ischemic injury is the evaluation of angiogenesis accompanying increased expression of integrin αvβ3. Here, we describe the capability of an αvβ3 integrin-targeting SPECT agent, 99mTc-IDA-D-[c(RGDfK)]2, for identification of ischemic but viable myocardium, i.e., hibernating myocardium which is crucial to predict functional recovery after revascularization, the standard care of cardiovascular medicine. In vivo SPECT imaging of rat models with transient coronary occlusion showed significantly high uptake of 99mTc-IDA-D-[c(RGDfK)]2 in the ischemic region. Comparative measurements with 201Tl SPECT and 18F-FDG PET, then, proved that such prominent uptake of 99mTc-IDA-D-[c(RGDfK)]2 exactly matched the hallmark of hibernation, i.e., the perfusion-metabolism mismatch pattern. The uptake of 99mTc-IDA-D-[c(RGDfK)]2 was non-inferior to that of 18F-FDG, confirmed by time-course variation analysis. Immunohistochemical characterization revealed that an intense signal of 99mTc-IDA-D-[c(RGDfK)]2 corresponded to the vibrant angiogenic events with elevated expression of αvβ3 integrin. Together, these results establish that 99mTc-IDA-D-[c(RGDfK)]2 SPECT can serve as a sensitive clinical measure for myocardial salvage to identify the patients who might benefit most from revascularization.
Highlights
Monitoring of cardiovascular disease (CVD) was based on techniques that measure changes in blood flow and cellular metabolism
After 7, 14, and 28 days, animals were subjected to single photon emission computed tomography (SPECT) and positron emission tomography (PET) imaging, and sacrificed for histological analyses (Fig. 1A)
SPECT scans were performed for 30 minutes after serial injection of 99mTcIDA-D-[c(RGDfK)]2 and 201Tl intravenously (IV), immediately followed by 20-min computed tomography (CT) scans (Fig. 1B). 18F-FDG PET/CT was conducted with the same animals at the day of SPECT/CT imaging performed
Summary
Monitoring of CVD was based on techniques that measure changes in blood flow and cellular metabolism. Considering high integrin-binding affinity, specific in vivo targeting, and desirable pharmacokinetic properties as shown in the previous studies[21,22], the developed RGD dimer agent is expected to be suitable to pinpoint hibernating myocardium which is clinically characterized by perfusion defect and enhanced FDG uptake. To prove such utility of 99mTc-IDA-D-[c(RGDfK)]2 SPECT imaging approach, we focused on in vivo imaging of transient coronary occlusion model to mimic reversible myocardial infarction and reperfusion in the clinical setting. We demonstrate a molecular imaging strategy that uses αvβ[3] integrin-targeted probe 99mTc-IDA-D-[c(RGDfK)]2 with SPECT to assess myocardial viability after ischemic injury to identify the patients who might benefit most from revascularization
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