Evangelos Tzolos

BACKGROUND: Determining the source of thromboembolism in patients with acute ischemic stroke remains challenging because current diagnostic approaches rely largely on circumstantial and inferential associations rather than direct identification of the cause of stroke. Fluorine-18 GP1 ([ ¹⁸ F]GP1) is a novel radiotracer that binds with high affinity and specificity to activated glycoprotein IIb/IIIa receptors on activated platelets. We aimed to determine whether hybrid [ ¹⁸ F]GP1 positron emission tomography (PET) and computed tomography angiography could identify in vivo cardiovascular thromboembolism in patients with acute ischemic stroke and provide a mechanism-based assessment of stroke etiology. METHODS: In a single-center prospective observational cohort study, 100 patients presenting with acute ischemic stroke underwent hybrid [ ¹⁸ F]GP1 PET/computed tomography angiography within 21 days of symptom onset in addition to standard-of-care stroke investigations. Stroke etiology was classified using the causative classification system by an expert stroke physician blinded to [ ¹⁸ F]GP1 PET findings. In parallel, [ ¹⁸ F]GP1 PET/computed tomography angiography images were analyzed independently by readers who were blinded to all clinical data and causative classification system classification. We assessed whether [ ¹⁸ F]GP1 PET/computed tomography angiography could identify the source of in vivo cardiovascular thromboembolism, influence stroke classification, and predict recurrent cerebrovascular events. RESULTS: Cardiovascular [ ¹⁸ F]GP1 uptake indicative of thrombosis was identified in nearly two-thirds (n=63) of participants, changing stroke classification in over a quarter (n=26) of patients. In those with stroke of undetermined cause, the source of thrombus was identified in 18 of 41 (44%) participants, which included nonstenotic carotid atherothrombosis, native cardiac valve thrombosis, and paradoxical thromboembolism. During a median follow-up of 613 (interquartile interval, 251–788) days, recurrent stroke or transient ischemic attack occurred in 14 patients, 13 (93%) of whom had cardiovascular [ ¹⁸ F]GP1 uptake at baseline. Cardiovascular [ ¹⁸ F]GP1 uptake was associated with a 10.4-fold increased risk of recurrent events (95% CI, 1.35–79.40; P =0.024). CONCLUSIONS: Noninvasive thrombosis imaging is a novel technique that enables direct in vivo identification of thrombus formation and frequently reveals the source of thromboembolism in patients with acute ischemic stroke. This approach represents a shift from inference-based to mechanism-based stroke classification with potential implications for targeted prevention strategies and better patient outcomes. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique Identifier: NCT05636748.

Aims: Microvascular obstruction (MVO) remains a major complication following coronary reperfusion, but its pathogenesis is poorly defined. We evaluated myocardial platelet activation and thrombosis using fluorine-18-labelled GP1 ([18F]GP1) positron emission tomography (PET) in patients with anterior ST-segment elevation myocardial infarction. Methods and results: In a single-centre observational cohort study, 100 patients with acute anterior ST-segment elevation myocardial infarction underwent hybrid cardiac [18F]GP1 PET and magnetic resonance (MR) imaging with gadolinium enhancement and repeat imaging at 3–6 months. Myocardial [18F]GP1 uptake was quantified using target-to-background ratio (TBRmax) and percentage myocardial uptake (burden) and compared with MR measures of infarction, MVO and adverse ventricular remodelling. One hundred patients (60 ± 10 years, 91% male) underwent [18F]GP1 PET/MR imaging at a median of 13 days following index presentation. Increased myocardial [18F]GP1 uptake was observed in 44% of participants (TBRmax 1.89 ± 0.50). All 40 patients with MR-defined MVO demonstrated myocardial [18F]GP1 uptake. Myocardial [18F]GP1 uptake burden correlated with (ρ = 0.84; P < 0.001), and exceeded (by 18%), MR-defined burden of MVO. Myocardial [18F]GP1 uptake was associated with infarct size, lower left ventricular ejection fraction and longer time-to-reperfusion. Angiographic no-reflow was the strongest independent association of MVO (adjusted odds ratio 16.15; P < 0.001). Persistent myocardial [18F]GP1 uptake at follow up (22%, 7/32) was associated with lower left ventricular ejection fraction. Resolution of cardiac MR-defined MVO was observed in 78% of patients at follow-up and was universally concordant with resolution of myocardial [18F]GP1 uptake. Conclusion: MVO following ST-segment elevation myocardial infarction is universally associated with myocardial platelet activation, extending beyond structural abnormalities identified by cardiac MR. These findings are consistent with an important mechanistic contribution of platelet-mediated microvascular thrombosis to no-reflow and MVO, highlighting a potentially targetable biological pathway in a condition for which effective therapies remain elusive.

Aims: Quantitative assessment of carotid artery plaque on computed tomography (CT) may identify high-risk phenotypes associated with culprit lesions and subsequent ischaemic stroke or transient ischaemic attack. Methods and results: Carotid CT angiography was performed in 48 patients with acute ischaemic stroke or transient ischaemic attack within 21 days. Quantitative plaque assessment was performed in the proximal 6 cm of the internal and external carotid artery, distal 6 cm of the common carotid artery, and residual common carotid artery. Semi-automated quantification included assessment of non-calcified, calcified, low-attenuation, and total plaque, area and diameter stenosis, and peri-vascular adipose tissue attenuation. In 48 patients (mean age 71 ± 11 years, 67% male), 96 vessels were assessed with 30 (31%) identified as culprit vessels. Culprit internal carotid arteries had greater area [83 (65, 94) vs. 64 (55, 77)%] and diameter [56 (39, 74) vs. 32 (21, 48)%] stenosis and more non-calcified [563 (413, 965) vs. 428 (283 649) mm3, P = 0.04], low-attenuation [33.7 (6.9, 72.4) vs. 16.3 (3.35, 54.3) mm3, P = 0.01], and total [699 (455, 1057) vs. 492 (311, 809), P = 0.04] plaque. There was no difference in calcified plaque or peri-vascular adipose tissue attenuation between culprit and non-culprit internal carotid arteries. There were no differences in quantitative plaque or peri-vascular adipose tissue attenuation in the external carotid artery or common carotid artery. Conclusion: Carotid atherosclerotic plaque characteristics are the principal features associated with culprit plaques with little or no demonstrable relationship with calcified plaque or increased peri-vascular adipose tissue attenuation.

Background Inflammation plays a pivotal role in atherogenesis and is a causal risk factor for atherosclerotic cardiovascular disease. Non-invasive coronary CT angiography (CCTA) enables evaluation of coronary plaque phenotype. This study investigates the relationship between a comprehensive panel of inflammatory markers and short-term plaque progression on serial CCTA imaging, hypothesising that inflammation is associated with increased plaque volume. Methods A total of 161 patients aged ≥40 years with stable multivessel coronary artery disease were included, who underwent CCTA at baseline and 12 months follow-up. Baseline plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein and other inflammatory markers were measured. Plaque volumes were assessed using semiautomated software, calculating total, noncalcified, calcified and low-attenuation noncalcified plaque volumes. Linear regression models, adjusted for ASSIGN score, segment involvement score and body mass index, evaluated associations between inflammatory markers and plaque volume changes. Results The mean±SD age was 65.4±8.4 years, with 129 (80.6%) male participants. Baseline total plaque volume was 1394 (1036, 1993) mm³. After 12 months, total plaque volume changed by 78 (−114, 244) mm³. IL-6 levels were associated with a 4.9% increase in total plaque volume (95% CI: 0.9 to 8.9, p=0.018) and a 4.8% increase in noncalcified plaque volume (95% CI: 0.7 to 8.9, p=0.022). No significant associations were observed for other inflammatory markers. Conclusions Plasma IL-6 levels are significantly associated with increased total and noncalcified short-term plaque progression in patients with stable coronary artery disease. This supports the potential of IL-6 as a target for reducing plaque progression and cardiovascular risk.

Background: Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. Methods and Results: In a double‐blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F‐sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24‐month change in coronary calcium score, and 12‐month changes in thoracic aorta calcium score, coronary and aortic 18F‐sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [−64 to 148] Agatston units) and either denosumab (94 [0–212] Agatston units, P =0.24) or alendronic acid (34 [−62 to 134], P =0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22–512] Agatston units) and either denosumab (118 [11–340], P =0.75) or alendronic acid (116 [26–498] Agatston units, P =0.62). There were no differences in changes in coronary or aortic 18F‐sodium fluoride activity between treatment groups. Conclusions: Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. registration: https://www.clinicaltrials.gov ; Unique identifier: NCT02132026.

Suvasini Lakshmanan, MD, MS, Evangelos Tzolos, MD, PhD, Jeffrey Kroon, PhD, Erik S G Stroes, MD, PhD, Kang H Zheng, MD, PhD, Damini Dey, PhD, Michelle C Wi