D Atherosclerotic inflammation imaging using 68ga-dotatate pet vs. 18f-fdg pet: a prospective clinical sudy with molecular and histological validation

    loading  Checking for direct PDF access through Ovid


BackgroundInflammation drives atherosclerotic plaque rupture underlying most clinical events. While inflammation can be measured using 18F-fluorodeoxyglucose (FDG) positron emission tomography (PET), 18F-FDG lacks cell-specificity and is unreliable for coronary imaging owing to myocardial signal spillover. Up-regulation of somatostatin receptor-2 (SST2) occurs in activated macrophages offering a novel inflammation imaging target.MethodsWe comprehensively evaluated 68Ga-DOTATATE, a SST2 PET ligand, for imaging atherosclerosis. Target SSTR2 gene expression in macrophages and other immune cells were tested using population-based RNA-sequencing data. Patients with atherosclerosis (n=42) underwent 68Ga-DOTATATE PET imaging in a prospective head-to-head comparison with 18F-FDG. 68Ga-DOTATATE autoradiography, immunostaining and quantitative PCR were performed in macrophages and excised carotid specimens from patients who underwent PET imaging.ResultsTarget SSTR2 expression occurred exclusively in “pro-inflammatory” M1 macrophages, and no other cell type studied in vitro. In clinical imaging, 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit vs. non-culprit arteries in patients with acute coronary syndrome (median difference 0.69 [IQR 0.22 to 1.15], p=0.008) and transient ischaemic attack or stroke (median difference 0.13 [IQR 0.07 to 0.32], p=0.003). 68Ga-DOTATATE mTBRmax accurately predicted stable non-culprit coronary lesions with high-risk CT features (ROC AUC 0.86 [95% CI 0.80 to 0.92], p<0.0001), and correlated with Framingham risk score (r=0.53 [95% CI 0.32 to 0.69], p<0.0001) and vascular inflammation defined by 18F-FDG (r=0.73 [95% CI 0.64 to 0.81], p<0.0001). While 18F-FDG mTBRmax also differentiated culprit from non-culprit carotid lesions (median difference 0.12 [IQR 0.0 to 0.23], p=0.008) and high-risk from lower-risk coronary lesions (ROC AUC 0.76 [95% CI 0.62 to 0.91], p=0.002), myocardial 18F-FDG spillover rendered coronary 18F-FDG scans uninterpretable in 27 (64%) patients. In contrast, low myocardial 68Ga-DOTATATE binding allowed unimpeded coronary signal interpretation in all patients without the need for pre-scan fasting. Moreover, histological analysis confirmed specific binding of 68Ga-DOTATATE to SST2 receptors expressed by CD68-positive macrophages in excised carotid plaques. Carotid SSTR2 mRNA was highly correlated with both CD68 mRNA (r=0.93 [95% CI 0.49 to 0.99]; p=0.007) and in vivo 68Ga-DOTATATE PET signals measured from clinical images (r=0.89 [95% CI 0.28 to 0.99], p=0.02).ConclusionWe provide gene, cell, plaque and patient-level data, demonstrating that SST2 PET imaging using 68Ga-DOTATATE represents a macrophage-specific marker of atherosclerotic inflammation that outperforms 18F-FDG in the coronary arteries. Future research will explore the utility of 68Ga-DOTATATE inflammation imaging to classify high-risk patients for aggressive therapeutic intervention.

    loading  Loading Related Articles