BackgroundInflammation drives atherosclerotic plaque rupture. Although inflammation can be measured using fluorine-18-labeled fluorodeoxyglucose positron emission tomography ([18F]FDG PET), [18F]FDG lacks cell specificity, and coronary imaging is unreliable because of myocardial spillover.ObjectivesThis study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation.MethodsWe confirmed 68Ga-DOTATATE binding in macrophages and excised carotid plaques. 68Ga-DOTATATE PET imaging was compared to [18F]FDG PET imaging in 42 patients with atherosclerosis.ResultsTarget SSTR2 gene expression occurred exclusively in “proinflammatory” M1 macrophages, specific 68Ga-DOTATATE ligand binding to SST2 receptors occurred in CD68-positive macrophage-rich carotid plaque regions, and carotid SSTR2 mRNA was highly correlated with in vivo 68Ga-DOTATATE PET signals (r = 0.89; 95% confidence interval [CI]: 0.28 to 0.99; p = 0.02). 68Ga-DOTATATE mean of maximum tissue-to-blood ratios (mTBRmax) correctly identified culprit versus nonculprit arteries in patients with acute coronary syndrome (median difference: 0.69; interquartile range [IQR]: 0.22 to 1.15; p = 0.008) and transient ischemic attack/stroke (median difference: 0.13; IQR: 0.07 to 0.32; p = 0.003). 68Ga-DOTATATE mTBRmax predicted high-risk coronary computed tomography features (receiver operating characteristics area under the curve [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 [18F]FDG uptake (r = 0.73; 95% CI: 0.64 to 0.81; p < 0.0001). [18F]FDG mTBRmax differentiated culprit from nonculprit carotid lesions (median difference: 0.12; IQR: 0.0 to 0.23; p = 0.008) and high-risk from lower-risk coronary arteries (ROC AUC: 0.76; 95% CI: 0.62 to 0.91; p = 0.002); however, myocardial [18F]FDG spillover rendered coronary [18F]FDG scans uninterpretable in 27 patients (64%). Coronary 68Ga-DOTATATE PET scans were readable in all patients.ConclusionsWe validated 68Ga-DOTATATE PET as a novel marker of atherosclerotic inflammation and confirmed that 68Ga-DOTATATE offers superior coronary imaging, excellent macrophage specificity, and better power to discriminate high-risk versus low-risk coronary lesions than [18F]FDG. (Vascular Inflammation Imaging Using Somatostatin Receptor Positron Emission Tomography [VISION]; NCT02021188)

SummaryBackgroundIntensive antiplatelet therapy with three agents might be more effective than guideline treatment for preventing recurrent events in patients with acute cerebral ischaemia. We aimed to compare the safety and efficacy of intensive antiplatelet therapy (combined aspirin, clopidogrel, and dipyridamole) with that of guideline-based antiplatelet therapy.MethodsWe did an international, prospective, randomised, open-label, blinded-endpoint trial in adult participants with ischaemic stroke or transient ischaemic attack (TIA) within 48 h of onset. Participants were assigned in a 1:1 ratio using computer randomisation to receive loading doses and then 30 days of intensive antiplatelet therapy (combined aspirin 75 mg, clopidogrel 75 mg, and dipyridamole 200 mg twice daily) or guideline-based therapy (comprising either clopidogrel alone or combined aspirin and dipyridamole). Randomisation was stratified by country and index event, and minimised with prognostic baseline factors, medication use, time to randomisation, stroke-related factors, and thrombolysis. The ordinal primary outcome was the combined incidence and severity of any recurrent stroke (ischaemic or haemorrhagic; assessed using the modified Rankin Scale) or TIA within 90 days, as assessed by central telephone follow-up with masking to treatment assignment, and analysed by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN47823388.Findings3096 participants (1556 in the intensive antiplatelet therapy group, 1540 in the guideline antiplatelet therapy group) were recruited from 106 hospitals in four countries between April 7, 2009, and March 18, 2016. The trial was stopped early on the recommendation of the data monitoring committee. The incidence and severity of recurrent stroke or TIA did not differ between intensive and guideline therapy (93 [6%] participants vs 105 [7%]; adjusted common odds ratio [cOR] 0·90, 95% CI 0·67–1·20, p=0·47). By contrast, intensive antiplatelet therapy was associated with more, and more severe, bleeding (adjusted cOR 2·54, 95% CI 2·05–3·16, p<0·0001).InterpretationAmong patients with recent cerebral ischaemia, intensive antiplatelet therapy did not reduce the incidence and severity of recurrent stroke or TIA, but did significantly increase the risk of major bleeding. Triple antiplatelet therapy should not be used in routine clinical practice.FundingNational Institutes of Health Research Health Technology Assessment Programme, British Heart Foundation.

Atherosclerosis is a leading cause of morbidity and mortality. It is now widely recognized that the disease is more than simply a flow-limiting process and that the atheromatous plaque represents a nidus for inflammation with a consequent risk of plaque rupture and atherothrombosis, leading to myocardial infarction or stroke. However, widely used conventional clinical imaging techniques remain anatomically focused, assessing only the degree of arterial stenosis caused by plaques. Positron emission tomography (PET) has allowed the metabolic processes within the plaque to be detected and quantified directly. The increasing armory of radiotracers has facilitated the imaging of distinct metabolic aspects of atherogenesis and plaque destabilization, including macrophage-mediated inflammatory change, hypoxia, and microcalcification. This imaging modality has not only furthered our understanding of the disease process in vivo with new insights into mechanisms but has also been utilized as a non-invasive endpoint measure in the development of novel treatments for atherosclerotic disease. This review provides grounding in the principles of PET imaging of atherosclerosis, the radioligands in use and in development, its research and clinical applications, and future developments for the field.

AimsThe association of coronary arterial calcification with cardiovascular morbidity and mortality is well-recognized. Lower limb arterial calcification (LLAC) is common in PAD but its impact on subsequent health is poorly described. We aimed to determine the association between a LLAC score and subsequent cardiovascular events in patients with symptomatic peripheral arterial disease (PAD).MethodsLLAC scoring, and the established Bollinger score, were derived from a database of unenhanced CT scans, from patients presenting with symptomatic PAD. We determined the association between these scores outcomes. The primary outcome was combined cardiac mortality and morbidity (CM/M) with a secondary outcome of all-cause mortality.Results220 patients (66% male; median age 69 years) were included with follow-up for a median 46 [IQR 31–64] months. Median total LLAC scores were higher in those patients suffering a primary outcome (6831 vs. 1652; p = 0.012). Diabetes mellitus (p = 0.039), ischaemic heart disease (p = 0.028), chronic kidney disease (p = 0.026) and all-cause mortality (p = 0.012) were more common in patients in the highest quartile of LLAC scores. The area under the curve of the receiver operator curve for the LLAC score was greater (0.929: 95% CI [0.884–0.974]) than for the Bollinger score (0.824: 95% CI [0.758–0.890]) for the primary outcome. A LLAC score ≥ 4400 had the best diagnostic accuracy to determine the outcome measure.ConclusionThis is the largest study to investigate links between lower limb arterial calcification and cardiovascular events in symptomatic PAD. We describe a straightforward, reproducible, CT-derived measure of calcification—the LLAC score.