PAR4 Antagonism in Patients With Coronary Artery Disease Receiving Antiplatelet Therapies.

BACKGROUND: BMS-986141 is a novel potent highly selective antagonist of PAR (protease-activated receptor) type 4. PAR4 antagonism has been demonstrated to reduce thrombus formation in isolation and in combination with factor Xa inhibition in high shear conditions in healthy people. We sought to determine whether PAR4 antagonism had additive antithrombotic effects in patients with coronary artery disease who were receiving antiplatelet therapy. METHODS: Forty-five patients with stable coronary heart disease and 10 healthy volunteers completed a phase 2a open-label 4-arm single-center study. Patients were allocated to 1 of 3 treatment arms for 7 days: (1) ticagrelor (90 mg BID), (2) aspirin (75 mg QD), or (3) the combination of ticagrelor and aspirin. Agonist-induced platelet aggregation, platelet activation, and ex vivo thrombus formation were measured before and 2 and 24 hours after a single oral 4-mg dose of BMS-986141 on the first study visit day in all participants. RESULTS: BMS-986141 demonstrated highly selective inhibition of PAR4-AP (agonist peptide)-induced platelet aggregation, P-selectin expression, and platelet-monocyte aggregate expression (P≤0.001 for all), which were unaffected by concomitant antiplatelet therapies. PAR4 antagonism reduced ex vivo thrombus area in high shear conditions in healthy volunteers (-21%; P=0.001) and in patients receiving ticagrelor alone (-28%; P=0.001), aspirin alone (-23%; P=0.018), or both in combination (-24%; P≤0.001). Plasma concentration of BMS-986141 correlated with PAR4-AP-induced platelet responses (P≤0.001 for all) and total thrombus area under high shear stress conditions (P≤0.01 for all). CONCLUSIONS: PAR4 antagonism has additive antithrombotic effects when used in addition to ticagrelor, aspirin, or their combination, in patients with stable coronary heart disease. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT05093790.

Thoracic aortic microcalcification activity in combined positron emission tomography and magnetic resonance imaging.

INTRODUCTION: Non-invasive detection of pathological changes in thoracic aortic disease remains an unmet clinical need particularly for patients with congenital heart disease. Positron emission tomography combined with magnetic resonance imaging (PET-MRI) could provide a valuable low-radiation method of aortic surveillance in high-risk groups. Quantification of aortic microcalcification activity using sodium [18F]fluoride holds promise in the assessment of thoracic aortopathies. We sought to evaluate aortic sodium [18F]fluoride uptake in PET-MRI using three methods of attenuation correction compared to positron emission tomography computed tomography (PET-CT) in patients with bicuspid aortic valve, METHODS: Thirty asymptomatic patients under surveillance for bicuspid aortic valve disease underwent sodium [18F]fluoride PET-CT and PET-MRI of the ascending thoracic aorta during a single visit. PET-MRI data were reconstructed using three iterations of attenuation correction (Dixon, radial gradient recalled echo with two [RadialVIBE-2] or four [RadialVIBE-4] tissue segmentation). Images were qualitatively and quantitatively analysed for aortic sodium [18F]fluoride uptake on PET-CT and PET-MRI. RESULTS: Aortic sodium [18F]fluoride uptake on PET-MRI was visually comparable with PET-CT using each reconstruction and total aortic standardised uptake values on PET-CT strongly correlated with each PET-MRI attenuation correction method (Dixon R = 0.70; RadialVIBE-2 R = 0.63; RadialVIBE-4 R = 0.64; p < 0.001 for all). Breathing related artefact between soft tissue and lung were detected using Dixon and RadialVIBE-4 but not RadialVIBE-2 reconstructions, with the presence of this artefact adjacent to the atria leading to variations in blood pool activity estimates. Consequently, quantitative agreements between radiotracer activity on PET-CT and PET-MRI were most consistent with RadialVIBE-2. CONCLUSION: Ascending aortic microcalcification analysis in PET-MRI is feasible with comparable findings to PET-CT. RadialVIBE-2 tissue attenuation correction correlates best with the reference standard of PET-CT and is less susceptible to artefact. There remain challenges in segmenting tissue types in PET-MRI reconstructions, and improved attenuation correction methods are required.

18F-NaF PET/MRI for Detection of Carotid Atheroma in Acute Neurovascular Syndrome.

Background MRI and fluorine 18-labeled sodium fluoride (18F-NaF) PET can be used to identify features of plaque instability, rupture, and disease activity, but large studies have not been performed. Purpose To evaluate the association between 18F-NaF activity and culprit carotid plaque in acute neurovascular syndrome. Materials and Methods In this prospective observational cohort study (October 2017 to January 2020), participants underwent 18F-NaF PET/MRI. An experienced clinician determined the culprit carotid artery based on symptoms and record review. 18F-NaF uptake was quantified using standardized uptake values and tissue-to-background ratios. Statistical significance was assessed with the Welch, χ2, Wilcoxon, or Fisher test. Multivariable models were used to evaluate the relationship between the imaging markers and the culprit versus nonculprit vessel. Results A total of 110 participants were evaluated (mean age, 68 years ± 10 [SD]; 70 men and 40 women). Of the 110, 34 (32%) had prior cerebrovascular disease, and 26 (24%) presented with amaurosis fugax, 54 (49%) with transient ischemic attack, and 30 (27%) with stroke. Compared with nonculprit carotids, culprit carotids had greater stenoses (≥50% stenosis: 30% vs 15% [P = .02]; ≥70% stenosis: 25% vs 4.5% [P < .001]) and had increased prevalence of MRI-derived adverse plaque features, including intraplaque hemorrhage (42% vs 23%; P = .004), necrotic core (36% vs 18%; P = .004), thrombus (7.3% vs 0%; P = .01), ulceration (18% vs 3.6%; P = .001), and higher 18F-NaF uptake (maximum tissue-to-background ratio, 1.38 [IQR, 1.12-1.82] vs 1.26 [IQR, 0.99-1.66], respectively; P = .04). Higher 18F-NaF uptake was positively associated with necrosis, intraplaque hemorrhage, ulceration, and calcification and inversely associated with fibrosis (P = .04 to P < .001). In multivariable analysis, carotid stenosis at or over 70% (odds ratio, 5.72 [95% CI: 2.2, 18]) and MRI-derived adverse plaque characteristics (odds ratio, 2.16 [95% CI: 1.2, 3.9]) were both associated with the culprit versus nonculprit carotid vessel. Conclusion Fluorine 18-labeled sodium fluoride PET/MRI characteristics were associated with the culprit carotid vessel in study participants with acute neurovascular syndrome. Clinical trial registration no. NCT03215550 and NCT03215563 © RSNA, 2022 Online supplemental material is available for this article.

CT Attenuation of Periaortic Adipose Tissue in Abdominal Aortic Aneurysms.

Purpose To assess periaortic adipose tissue attenuation at CT angiography in different abdominal aortic aneurysm disease states. Materials and Methods In a retrospective observational study from January 2018 to December 2022, periaortic adipose tissue attenuation was assessed at CT angiography in patients with asymptomatic or symptomatic (including rupture) abdominal aortic aneurysms and controls without aneurysms. Adipose tissue attenuation was measured using semiautomated software in periaortic aneurysmal and nonaneurysmal segments of the abdominal aorta and in subcutaneous and visceral adipose tissue. Periaortic adipose tissue attenuation values between the three groups were assessed using Student t tests and Wilcoxon rank sum tests followed by a multiregression model. Results Eighty-eight individuals (median age, 70 years [IQR, 65-78]; 78 male and 10 female patients) were included: 70 patients with abdominal aortic aneurysms (40 asymptomatic and 30 symptomatic, including 24 with rupture) and 18 controls. There was no evidence of differences in the periaortic adipose tissue attenuation in the aneurysmal segment in asymptomatic patients versus controls (-81.44 HU ± 7 [SD] vs -83.27 HU ± 9; P = .43) and attenuation in nonaneurysmal segments between asymptomatic patients versus controls (-75.43 HU ± 8 vs -78.81 HU ± 6; P = .08). However, symptomatic patients demonstrated higher periaortic adipose tissue attenuation in both aneurysmal (-57.85 HU ± 7; P < .0001) and nonaneurysmal segments (-58.16 HU ± 8; P < .0001) when compared with the other two groups. Conclusion Periaortic adipose tissue CT attenuation was not increased in stable abdominal aortic aneurysm disease. There was a generalized increase in attenuation in patients with symptomatic disease, likely reflecting the systemic consequences of acute rupture. Keywords: Abdominal Aortic Aneurysm, Periaortic Adipose Tissue Attenuation, CT Angiography ClinicalTrials.gov registration no. NCT02229006 © RSNA, 2024.

Aortic sodium [18F]fluoride uptake following endovascular aneurysm repair.

OBJECTIVE: In patients with abdominal aortic aneurysms, sodium [18F]fluoride positron emission tomography identifies aortic microcalcification and disease activity. Increased uptake is associated with aneurysm expansion and adverse clinical events. The effect of endovascular aneurysm repair (EVAR) on aortic disease activity and sodium [18F]fluoride uptake is unknown. This study aimed to compare aortic sodium [18F]fluoride uptake before and after treatment with EVAR. METHODS: In a preliminary proof-of-concept cohort study, preoperative and post-operative sodium [18F]fluoride positron emission tomography-computed tomography angiography was performed in patients with an infrarenal abdominal aortic aneurysm undergoing EVAR according to current guideline-directed size treatment thresholds. Regional aortic sodium [18F]fluoride uptake was assessed using aortic microcalcification activity (AMA): a summary measure of mean aortic sodium [18F]fluoride uptake. RESULTS: Ten participants were recruited (76±6 years) with a mean aortic diameter of 57±2 mm at time of EVAR. Mean time from EVAR to repeat scan was 62±21 months. Prior to EVAR, there was higher abdominal aortic AMA when compared with the thoracic aorta (AMA 1.88 vs 1.2; p<0.001). Following EVAR, sodium [18F]fluoride uptake was markedly reduced in the suprarenal (ΔAMA 0.62, p=0.03), neck (ΔAMA 0.72, p=0.02) and body of the aneurysm (ΔAMA 0.69, p=0.02) while it remained unchanged in the thoracic aorta (ΔAMA 0.11, p=0.41). CONCLUSIONS: EVAR is associated with a reduction in AMA within the stented aortic segment. This suggests that EVAR can modify aortic disease activity and aortic sodium [18F]fluoride uptake is a promising non-invasive surrogate measure of aneurysm disease activity.

Quantifying sodium [18F]fluoride uptake in abdominal aortic aneurysms.

BACKGROUND: Aortic microcalcification activity is a recently described method of measuring aortic sodium [18F]fluoride uptake in the thoracic aorta on positron emission tomography. In this study, we aimed to compare and to modify this method for use within the infrarenal aorta of patients with abdominal aortic aneurysms. METHODS: Twenty-five patients with abdominal aortic aneurysms underwent an sodium [18F]fluoride positron emission tomography and computed tomography scan. Maximum and mean tissue-to-background ratios (TBR) and abdominal aortic microcalcification activity were determined following application of a thresholding and variable radius method to correct for vertebral sodium [18F]fluoride signal spill-over and the nonlinear changes in aortic diameter, respectively. Agreement between the methods, and repeatability of these approaches were assessed. RESULTS: The aortic microcalcification activity method was much quicker to perform than the TBR method (14 versus 40 min, p < 0.001). There was moderate-to-good agreement between TBR and aortic microcalcification activity measurements for maximum (interclass correlation co-efficient, 0.67) and mean (interclass correlation co-efficient, 0.88) values. These correlations sequentially improved with the application of thresholding (intraclass correlation coefficient 0.93, 95% confidence interval 0.89-0.95) and variable diameter (intraclass correlation coefficient 0.97, 95% confidence interval 0.94-0.99) techniques. The optimised method had good intra-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.36 and limits of agreement - 0.43 to 0.43) and inter-observer (mean 1.57 ± 0.42, bias 0.08, co-efficient of repeatability 0.47 and limits of agreement - 0.53 to 0.53) repeatability. CONCLUSIONS: Aortic microcalcification activity is a quick and simple method which demonstrates good intra-observer and inter-observer repeatabilities and provides measures of sodium [18F]fluoride uptake that are comparable to established methods.

18F-Sodium Fluoride Positron Emission Tomography and Computed Tomography in Acute Aortic Syndrome.

BACKGROUND: Acute aortic syndrome is associated with aortic medial degeneration. 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) detects microscopic tissue calcification as a marker of disease activity. OBJECTIVES: In a proof-of-concept study, this investigation aimed to establish whether 18F-NaF PET combined with computed tomography (CT) angiography could identify aortic medial disease activity in patients with acute aortic syndrome. METHODS: Patients with aortic dissection or intramural hematomas and control subjects underwent 18F-NaF PET/CT angiography of the aorta. Aortic 18F-NaF uptake was measured at the most diseased segment, and the maximum value was corrected for background blood pool activity (maximum tissue-to-background ratio [TBRmax]). Radiotracer uptake was compared with change in aortic size and major adverse aortic events (aortic rupture, aorta-related death, or aortic repair) over 45 ± 13 months. RESULTS: Aortic 18F-NaF uptake co-localized with histologically defined regions of microcalcification and elastin disruption. Compared with control subjects, patients with acute aortic syndrome had increased 18F-NaF uptake (TBRmax: 1.36 ± 0.39 [n = 20] vs 2.02 ± 0.42 [n = 47] respectively; P < 0.001) with enhanced uptake at the site of intimal disruption (+27.5%; P < 0.001). 18F-NaF uptake in the false lumen was associated with aortic growth (+7.1 mm/year; P = 0.011), and uptake in the outer aortic wall was associated with major adverse aortic events (HR: 8.5 [95% CI: 1.4-50.4]; P = 0.019). CONCLUSIONS: In patients with acute aortic syndrome, 18F-NaF uptake was enhanced at sites of disease activity and was associated with aortic growth and clinical events. 18F-NaF PET/CT holds promise as a noninvasive marker of disease severity and future risk in patients with acute aortic syndrome. (18F Sodium Fluoride PET/CT in Acute Aortic Syndrome [FAASt]; NCT03647566).

Thoracic Aortic 18F-Sodium Fluoride Activity and Ischemic Stroke in Patients With Established Cardiovascular Disease.

BACKGROUND: Aortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke. OBJECTIVES: The purpose of this study was to investigate whether thoracic 18F-sodium fluoride positron emission tomography (PET) could improve the identification of patients at the highest risk of ischemic stroke. METHODS: In a post hoc observational cohort study, we quantified thoracic aortic and coronary 18F-sodium fluoride activity in 461 patients with stable cardiovascular disease undergoing PET combined with computed tomography (CT). Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischemic stroke and myocardial infarction. We compared the prognostic utility of 18F-sodium fluoride activity for predicting stroke to clinical risk scores and CT calcium quantification using survival analysis and multivariable Cox regression. RESULTS: After 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n = 140; r = 0.31; P = 0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke and 32 (7%) a myocardial infarction after 6.1 ± 2.3 years of follow-up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischemic stroke (HR: 10.3 [95% CI: 3.1-34.8]; P = 0.00017), but not myocardial infarction (P = 0.40). Conversely, high coronary 18F-sodium fluoride activity was associated with myocardial infarction (HR: 4.8 [95% CI: 1.9-12.2]; P = 0.00095) but not ischemic stroke (P = 0.39). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was the only variable associated with ischemic stroke (HR: 8.19 [95% CI: 2.33-28.7], P = 0.0010). CONCLUSIONS: In patients with established cardiovascular disease, thoracic aortic 18F-sodium fluoride activity is associated with the progression of atherosclerosis and future ischemic stroke. Arterial 18F-sodium fluoride activity identifies localized areas of atherosclerotic disease activity that are directly linked to disease progression and downstream regional clinical atherothrombotic events. (DIAMOND-Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND], NCT02110303; Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis [SALTIRE II], NCT02132026; Novel Imaging Approaches To Identify Unstable Coronary Plaques, NCT01749254; and Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis, NCT01358513).

Endovascular repair for abdominal aortic aneurysms.

Management of abdominal aortic aneurysms has been the subject of rigorous scientific scrutiny. Prevalence studies have directed the formation of screening programmes, and observational studies and randomised controlled trials have defined aneurysm growth and treatment thresholds. Pre-emptive intervention with traditional open surgical repair has been the bedrock of improving long-term outcome and survival in patients with abdominal aortic aneurysms but it is associated with a significant procedural morbidity and mortality. Endovascular aneurysm repair (EVAR) has substantially reduced these early complications and has been associated with promising results in both elective and emergency aneurysm repair. However, the technique has brought its own unique complications, endoleaks. An endoleak is the presence of blood flow within the aneurysm sac but outside the EVAR graft. Although in randomised control trials EVAR was associated with a reduced early mortality compared with open repair, its longer-term morbidity and mortality was higher because endoleak development is associated with a higher risk of rupture. These endoleak complications have necessitated the development of postoperative imaging surveillance and re-intervention. These contrasting benefits and risks inform the selection of the mode of repair and are heavily influenced by individual patient factors. An improved strategy to predict endoleak development could further help direct treatment choice for patients and improve both early and late outcomes. This article reviews current EVAR practice, recent updates in clinical practice guidelines and the potential future developments to facilitate the selection of mode of aneurysm repair.Trial registration number: ClinicalTrials.gov NCT04577716.

Flow cytometry and thromboelastography to assess platelet counts and coagulation in patients with haematological malignancies.

BACKGROUND: Accurate platelet counts (PC) are necessary in order to follow recommendations for prophylactic platelet transfusion. We carried out a study comparing the standard way of counting platelets using a routine analyser and compared it with PC determined by flow cytometry (FC) and haemostatic data obtained with thromboelastography (TEG). MATERIALS AND METHODS: The study was carried out on 24 patients with haematological malignancies, all given one adult dose of platelets. The PC was determined before and after transfusion using an automated blood cell counter and FC. Citrated, "native" whole blood TEG was carried out before and after platelet transfusion to assess global haemostasis. RESULTS: No bleeding was observed in any of the subjects. Thirty-one assessments were performed in the 24 patients. The mean pre-transfusion PC were 9.8 and 13×10(9)/L with the automated counter and FC, respectively with a difference of 3.7 (p=0.0011). Excellent correlation was observed between the two counts (r=0.89; p<0.0001). Mean post-transfusion increments were 23 and 29×10(9)/L for the routine counter and FC, respectively. Using the immunological PC, patients would not have qualified for transfusion in 18.2% of cases since their PC was >20×10(9)/L. TEG showed a shortened reaction time in 69.6% of cases and a normal mean K time of 6.7 min. Only 9% had a low α angle signifying hypocoagulability. The maximum amplitude was reduced in the majority of cases but normal in 25% despite PC<20×10(9)/L. Mean activated partial thromboplastin time, prothrombin time and fibrinogen were normal prior to transfusion. DISCUSSION: Although higher PC as assessed by FC could potentially have an impact on platelet transfusion practices, TEG was sensitive enough to detect PC<10×10(9)/L and some between 10-20×10(9)/L. Whether patients with the latter PC are more prone to bleeding remains to be verified in larger studies.