Abstract 4373120: Assessment of Adverse Left Ventricular Remodeling Following Ischemia Reperfusion Injury with SPECT Imaging Agent Targeting Fibroblast Activation Protein

Abstract

Background: While reperfusion significantly improves acute myocardial infarction (MI) survival rates, the process leads to an inflammatory cascade that upregulates fibrotic pathways and proliferation of cardiac fibroblasts. Targeted SPECT imaging of fibroblast activation protein (FAP) provides a means to non-invasively quantify activated fibroblasts in the remodeling myocardium. We aimed to explore the relation between myocardial strain, regional stress and fibroblast activation with a FAP SPECT radiotracer, 99m Tc-iFAP, in a post-ischemia reperfusion (IR) porcine model using a novel 360° Hybrid SPECT CZT/CT camera along with histological validation. Methods: Transmural IR injury was induced in n=5 swine by a 90-min balloon occlusion of the LAD. Global circumferential strain was assessed by 3D echocardiography at baseline and post-MI with LV hemodynamics. At 7-11 days post-MI, a hybrid SPECT/CT image was acquired 90 min following injection of 99m Tc-iFAP with infarct uptake delineated as the region two standard deviations above blood activity in the aorta. Contrast CT was used to define the myocardial borders, LV diameter and wall thickness for calculation of regional wall stress. Following euthanasia, hearts were quantitatively evaluated histologically for fibrosis, myofibroblasts, and FAP. Results: Global circumferential strain was significantly impaired post-MI (Fig.1A, p<0.01) with a significant increase in LVEDP (Fig.1B, p<0.05). Regional wall stress in the MI region was significantly elevated compared to the contralateral region (Fig.1C, p<0.05). 99m Tc-iFAP uptake in the infarct area was significantly elevated (Fig. 1D, p<0.01) and demonstrated significant correlation with an increase in regional wall stress (Fig.1E, R=0.75). These in vivo imaging findings were associated with an increase in fibrosis (Fig.1F), myofibroblasts (Fig.1G) and FAP (Fig.1H) in the infarcted LV compared to the non-infarcted LV as assessed by histological staining of the tissue postmortem. Conclusion: 99m Tc-iFAP uptake in the infarct region post ischemia/reperfusion had a significant direct correlation with increased regional wall stress and histological findings of active fibrosis in MI region. We have demonstrated that 99m Tc-iFAP uptake accurately defines the area of active cardiac remodeling with fibroblast activation which could be used for guiding and monitoring therapeutic interventions directed at modulating adverse post-MI remodeling.