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

Alexander J Fletcher, Yong Y Tew, Evangelos Tzolos, Shruti S Joshi, Jakub Kaczynski, Jennifer Nash, Samuel Debono, Maria Lembo, Jacek Kwiecinski, Rong Bing, Maaz B J Syed, Mhairi K Doris, Edwin J R van Beek, Alistair J Moss, William S Jenkins, Niki L Walker, Nikhil V Joshi, Tania A Pawade, Philip D Adamson, William N Whiteley, Joanna M Wardlaw, Piotr J Slomka, Michelle C Williams, David E Newby, Marc R Dweck, Alexander J Fletcher, Yong Y Tew, Evangelos Tzolos, Shruti S Joshi, Jakub Kaczynski, Jennifer Nash, Samuel Debono, Maria Lembo, Jacek Kwiecinski, Rong Bing, Maaz B J Syed, Mhairi K Doris, Edwin J R van Beek, Alistair J Moss, William S Jenkins, Niki L Walker, Nikhil V Joshi, Tania A Pawade, Philip D Adamson, William N Whiteley, Joanna M Wardlaw, Piotr J Slomka, Michelle C Williams, David E Newby, Marc R Dweck

Abstract

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).

Keywords: (18)F-sodium fluoride; calcification; computed tomography; positron emission tomography; stroke; thoracic aorta.

Conflict of interest statement

Funding Support and Author Disclosures Drs Fletcher (FS/19/15/34155), Tzolos (FS/17/51/33096), Syed (FS/18/31/33676), Moss (AA/18/3/34220), Walker (FS/19/15/34155), Williams (FS/ICRF/20/26002), Newby (CH/09/002, RG/16/10/32375, RE/18/5/34216), and Dweck (FS/14/78/31020) are supported by the British Heart Foundation. Dr Lembo is supported by the International PhD programme in Cardiovascular Pathophysiology and Therapeutics (CardioPaTh). Dr van Beek is supported by SINAPSE. Dr Adamson is supported by a Heart Foundation of New Zealand Senior Fellowship (1844). Dr Wardlaw is supported by the UK Dementia Research Institute (funded by the MRC, Alzheimer Society and Alzheimer Research UK). Dr Slomka and FusionQuant Development are supported by the National Institute of Health Grant HL135557 (PI: Dr Slomka); and his laboratory is supported by National Institutes of Health R01HL135557. Dr Newby is the recipient of a Wellcome Trust Senior Investigator Award (WT103782AIA); and holds investigator-initiated research grants from Siemens Healthineers. Dr Dweck is the recipient of the Sir Jules Thorn Award for Biomedical Research 2015 (15/JTA). The Edinburgh Imaging facility QMRI (Edinburgh) is supported by the National Health Service Research Scotland through National Health Service Lothian Health Board. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.

Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.

Figures

Graphical abstract
Graphical abstract
Figure 1
Figure 1
Thoracic Aortic 18F-Sodium Fluoride Activity and Progression of Aortic Calcification Relationship between thoracic aortic 18F-sodium fluoride activity and progression of thoracic aortic calcium score (Agatston units [AU]). (A) Example case in which intense 18F-sodium fluoride activity on positron emission tomography and computed tomography (PET-CT) precedes areas of macrocalcification on computed tomography. (B) Example case of low 18F-sodium fluoride activity and minimal progression of macrocalcification on computed tomography. TBR = tissue-to-background ratio.
Figure 2
Figure 2
Receiver-Operating Characteristic Curves for Prediction of Stroke Area under the curve (AUC) for (A) 10-year stroke clinical risk score, (B) thoracic aortic 18F-sodium fluoride activity, and (C) thoracic aortic calcium score for the outcome of stroke. (D) AUC analysis comparing thoracic aortic 18F-sodium fluoride activity, clinical risk score, and thoracic aortic calcium score.
Figure 3
Figure 3
Aortic and Coronary 18F-Sodium Fluoride Activity and the Risk of Stroke and Myocardial Infarction Cumulative incidence curves demonstrating freedom from stroke (A and C) or myocardial infarction (B and D) across the combined cohort. (A) Thoracic aortic 18F-sodium fluoride activity threshold of ≥1.1 (n = 461) is strongly associated with future stroke (HR: 10.3 [95% CI: 3.1-34.8]; P = 0.00017), (B) but not myocardial infarction (HR: 1.35 [95% CI: 0.67-2.7]; P = 0.40). (C) Coronary 18F-sodium fluoride activity (n = 382, threshold 1.56) is not associated with future stroke (HR: 1.59 [95% CI: 0.56-4.53] P = 0.39) (D) but is strongly associated with future myocardial infarction (HR: 4.8 [95% CI: 1.9-12.2]; P = 0.00095). P values represent log-rank test.
Figure 4
Figure 4
Predictors of Stroke Univariable Cox regression including clinical variables previously associated with stroke in the revised Framingham stroke risk score and imaging parameters. Multivariable Cox regression models including 10-year revised Framingham stroke risk, thoracic aortic calcium score, and thoracic aortic 18F-sodium fluoride activity, both as a continuous (middle plot) or binary (bottom plot) variable. Thoracic aortic 18F-sodium fluoride activity is the only variable associated with stroke in either multivariable model.
Central Illustration
Central Illustration
Thoracic 18F-Sodium Fluoride Identifies Cardiovascular Risk in a Territory-Specific Manner A total of 461 patients underwent thoracic 18F-sodium fluoride positron emission tomography and computed tomography (PET-CT), allowing the calculation of both thoracic aortic and coronary 18F-sodium fluoride activity. After a mean of 6 years, high thoracic aortic 18F-sodium fluoride was associated with ischemic stroke, but not myocardial infarction. High coronary 18F-sodium fluoride was associated with myocardial infarction but not stroke.
Figure 5
Figure 5
Example of Association Between 18F-Sodium Fluoride Positron Emission Tomography and Future Stroke Baseline noncontrast computed tomography (CT) and 18F-sodium fluoride positron emission tomography (PET) of the aortic arch (A and B) and ascending aorta (C and D). A 60-year-old patient with hypertension and moderate aortic stenosis, on aspirin and clopidogrel. Overall low clinical risk score and thoracic aortic calcium scores, but high thoracic aortic 18F-sodium fluoride activity. Patient had bilateral posterior circulation infarcts at day 218 of follow-up with normal carotid arteries and no atrial fibrillation. AoArch = aortic arch; AoRoot = aortic root; AscAo = ascending aorta; AU = Agatston units; BCA = brachiocephalic artery; LScA = left subclavian artery; LV = left ventricle; Ra = right atrium; rFRS10 = Revised 10-year Framingham Stroke Risk Score; RPA = right pulmonary artery; other abbreviation as in Figure 1.

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