Nicholas R. Evans

Detection of Atherosclerotic Inflammation by 68Ga-DOTATATE PET Compared to [18F]FDG PET Imaging

Background Inflammation 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. Objectives This study tested the efficacy of gallium-68-labeled DOTATATE (68Ga-DOTATATE), a somatostatin receptor subtype-2 (SST2)-binding PET tracer, for imaging atherosclerotic inflammation. Methods We 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. Results Target 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. Conclusions We 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)

PET Imaging of Atherosclerotic Disease: Advancing Plaque Assessment from Anatomy to Pathophysiology.

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.

Molecular imaging of atherosclerosis with integrated PET imaging

Atherosclerotic diseases account for nearly half of all deaths and are leading causes of adult disability. Our understanding of how atherosclerosis leads to cardiovascular disease events has evolved: from a concept of progressive luminal narrowing, to that of sudden rupture and thrombosis of biologically active atheroma. In concert with this conceptual shift, contemporary imaging techniques now allow imaging of biological processes that associate with plaque instability: active calcification and plaque inflammation. This review focuses on opportunities provided by positron emission tomography/computed tomography, to identify these high-risk biological features of atherosclerosis.

Managing Risk After Intracerebral Hemorrhage in Concomitant Atrial Fibrillation and Cerebral Amyloid Angiopathy

A 77-year-old right-handed functionally independent man presented after waking with a right-sided frontal headache, associated with 3 episodes of vomiting. His headache progressed during the following 20 minutes, prompting presentation to the Emergency Department. He reported an unsteady gait but no focal weakness or sensory disturbance. He was known to be in atrial fibrillation (AF), for which he was anticoagulated with warfarin. His other comorbidities included a previous pulmonary embolus, hypertension, and benign prostatic hypertrophy. On examination, there was no focal neurological deficit, and his Glasgow Coma Scale score was 15. In view of his severe headache while therapeutically anticoagulated, he was investigated with an urgent computed tomography scan of his head. This demonstrated a 58 by 37 mm right temporal lobe hemorrhage (Figure 1). His international normalized ratio on admission was 2.13, which was corrected with vitamin K and prothrombin complex. The hemorrhage was managed conservatively with blood pressure control, initially requiring a labetalol infusion followed by oral lisinopril and doxazosin. Figure 1. Noncontrast axial computed tomography of head showing a right temporal lobe intracerebral hemorrhage (maximum diameter 58×37 mm) and associated mass effect with sulcal effacement. He remained neurologically stable throughout his admission. He was discharged 14 days later with a minor deficit in short-term memory but no other focal neurological deficit. His modified Rankin score was 1. In view of the acute hemorrhage, anticoagulation was withheld because further hemorrhagic risk was deemed to outweigh antithrombotic benefit. Magnetic resonance imaging was performed 1 month after discharge and demonstrated evolution of the hematoma (Figure 2A and 2B). Gradient echo images also demonstrated a small right parietal lobe hemorrhage (Figure 2C). These findings were suggestive of cerebral amyloid angiopathy (CAA) as the cause of his presenting right temporal lobe hemorrhage. Figure 2. Magnetic resonance imaging (MRI) of head performed 1 month after intracerebral hemorrhage. …

PET imaging of the neurovascular interface in cerebrovascular disease.

Cerebrovascular disease encompasses a range of pathologies that affect different components of the cerebral vasculature and brain parenchyma. Large artery atherosclerosis, acute cerebral ischaemia, and intracerebral small vessel disease all demonstrate altered metabolic processes that are key to their pathogenesis. Although structural imaging techniques such as MRI are the mainstay of clinical care and research in cerebrovascular disease, they have limited ability to detect these pathophysiological processes in vivo. By contrast, PET can detect and quantify metabolic processes that are relevant to each facet of cerebrovascular disease. Information obtained from PET studies has helped to shape the understanding of key concepts in cerebrovascular medicine, including vulnerable atherosclerotic plaque, salvageable ischaemic penumbra, neuroinflammation and selective neuronal loss after ischaemic insult. PET has also helped to elucidate the relationships between chronic hypoxia, neuroinflammation, and amyloid-β deposition in cerebral small vessel disease. This Review describes how PET-based imaging of metabolic processes at the neurovascular interface has contributed to our understanding of cerebrovascular disease.

Synthesis of Host Polymers and Guests for Electrophosphorescence

Significant progress has been realized in the design and synthesis of light emitting polymers that emit over the entire visible spectrum. However, up to seventy-five percent of charge recombination events can lead to triplet states that decay non-radiatively. Following the pioneering work in the field of small molecule organic light emitting devices, it has been found that solution processible iridium polymer complexes can be used to harness the wasted triplet energy. In this paper, new results with respect to the electrophosphorescence of solution processible tethered iridium polymer derivatives are presented. Furthermore, our approaches to the design of new high triplet energy conjugated polymer hosts are also reported.

18 F-FDG Uptake on PET/CT in Symptomatic versus Asymptomatic Carotid Disease: a Meta-Analysis

Introduction The role of positron emission tomography (PET)/computed tomography (CT) in the determination of inflammation in arterial disease is not well defined. This can provide information about arterial wall inflammation in atherosclerotic disease, and may give insight into plaque stability. The aim of this review was to perform a meta-analysis of PET/CT with 18F-FDG (fluorodeoxyglucose) uptake in symptomatic and asymptomatic carotid artery disease. Methods This was a systematic review, following PRISMA guidelines, which interrogated the MEDLINE database from January 2001 to May 2017. The search combined the terms, “inflammation”, “FDG”, and “stroke”. The search criteria included all types of studies, with a primary outcome of the degree of arterial vascular inflammation determined by 18F-FDG uptake. Analysis involved an inverse weighted variance estimate of pooled data, using a random effects model. Results A total of 14 articles (539 patients) were included in the meta-analysis. Comparing carotid artery 18F-FDG uptake in symptomatic versus asymptomatic disease yielded a standard mean difference of 0.94 (95% CI 0.58–1.130; p < .0001; I2 = 65%). Conclusions PET/CT using 18F-FDG can demonstrate carotid plaque inflammation, and is a marker of symptomatic disease. Further studies are required to understand the clinical implication of PET/CT as a risk prediction tool.

Clinical frailty is independently associated with non-prescription of anticoagulants in older patients with atrial fibrillation: Frailty in atrial fibrillation

Anticoagulants are underused in older patients with atrial fibrillation (AF). Scoring systems, such as CHA2DS2‐VASc and HAS‐BLED, are recommended to guide clinicians in anticoagulation decisions, but patients’ frailty might be an underrecognized factor. We investigated the association between the Clinical Frailty Scale (CFS) and community anticoagulant prescribing habits in patients aged ≥75 years with AF admitted acutely to hospital.

Activated prothrombin complex in the management of direct thrombin inhibitor-associated intracerebral haemorrhage

NRE is supported by a Research Training Fellowship from The Dunhill Medical Trust [grant number RTF44/0114].

Running, ischaemic stroke and carotid artery dissection

Learning point for clinicians Internal carotid artery dissection may occur in young healthy adults following exercise. It is important to have a low degree of suspicion for such cases, particularly in younger patients without typical cerebrovascular risk factors, as delay in diagnosis and appropriate management may result in excess morbidity and mortality. A previously healthy 60-year-old right-handed male presented to the emergency department with sudden-onset expressive dysphasia, diplopia, right-arm numbness and loss of fine motor control with involuntary movements in his right arm following the completion of his first half marathon. The race itself had been uneventful, though the patient had taken only minimal fluid intake despite warm conditions. After completing the race, he experienced mild disorientation with the presenting symptoms developing 15 min later. His past medical and family histories were unremarkable. He was a former social smoker …