https://www.thelancet.com/pdfs/journals/lancet/PIIS0140-6736(13)61754-7.pdf

18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial

Calcification in Aortic Stenosis: The Skeleton Key

Background— 18F-Sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) are promising novel biomarkers of disease activity in aortic stenosis. We compared 18F-NaF and 18F-FDG uptake with histological characterization of the aortic valve and assessed whether they predicted disease progression.

Methods and Results— Thirty patients with aortic stenosis underwent combined positron emission and computed tomography using 18F-NaF and 18F-FDG radiotracers. In 12 patients undergoing aortic valve replacement surgery (10 for each tracer), radiotracer uptake (mean tissue/background ratio) was compared with CD68 (inflammation), alkaline phosphatase, and osteocalcin (calcification) immunohistochemistry of the excised valve. In 18 patients (6 aortic sclerosis, 5 mild, and 7 moderate), aortic valve computed tomography calcium scoring was performed at baseline and after 1 year. Aortic valve 18F-NaF uptake correlated with both alkaline phosphatase ( r =0.65; P =0.04) and osteocalcin ( r =0.68; P =0.03) immunohistochemistry. There was no significant correlation between 18F-FDG uptake and CD68 staining ( r =−0.43; P =0.22). After 1 year, aortic valve calcification increased from 314 (193–540) to 365 (207–934) AU ( P <0.01). Baseline 18F-NaF uptake correlated closely with the change in calcium score ( r =0.66; P <0.01), and this improved further ( r =0.75; P <0.01) when 18F-NaF uptake overlying computed tomography–defined macrocalcification was excluded. No significant correlation was noted between valvular 18F-FDG uptake and change in calcium score ( r =−0.11; P =0.66).

Conclusions— 18F-NaF uptake identifies active tissue calcification and predicts disease progression in patients with calcific aortic stenosis.

Clinical Trial Registration— URL: . Unique identifier: [NCT01358513][1].

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01358513&atom=%2Fcirccvim%2F7%2F2%2F371.atom

18F-sodium fluoride uptake is a marker of active calcification and disease progression in patients with aortic stenosis.

Calcific aortic valve stenosis (CAVS) is common in the ageing population and set to become an increasing economic and health burden. Once present, it inevitably progresses and has a poor prognosis in symptomatic patients. No medical therapies are proven to be effective in holding or reducing disease progression. Therefore, aortic valve replacement remains the only available treatment option. Improved knowledge of the mechanisms underlying disease progression has provided us with insights that CAVS is not a passive disease. Rather, CAVS is regulated by numerous mechanisms with a key role for calcification. Aortic valve calcification (AVC) is actively regulated involving cellular and humoral factors that may offer targets for diagnosis and intervention. The discovery that the vitamin K-dependent proteins are involved in the inhibition of AVC has boosted our mechanistic understanding of this process and has opened up novel avenues in disease exploration. This review discusses processes involved in CAVS progression, with an emphasis on recent insights into calcification, methods for imaging calcification activity, and potential therapeutic options.

/pdf/calcific-aortic-valve-stenosis-hard-disease-in-the-heart-a-480afgeuxl.pdf

Calcific aortic valve stenosis: hard disease in the heart: A biomolecular approach towards diagnosis and treatment.

Major focus has been placed on the identification of vulnerable plaques as a means of improving the prediction of myocardial infarction. However, this strategy has recently been questioned on the basis that the majority of these individual coronary lesions do not in fact go on to cause clinical events. Attention is, therefore, shifting to alternative imaging modalities that might provide a more complete pan-coronary assessment of the atherosclerotic disease process. These include markers of disease activity with the potential to discriminate between patients with stable burnt-out disease that is no longer metabolically active and those with active atheroma, faster disease progression, and increased risk of infarction. This review will examine how novel molecular imaging approaches can provide such assessments, focusing on inflammation and microcalcification activity, the importance of these processes to coronary atherosclerosis, and the advantages and challenges posed by these techniques.

Noninvasive Molecular Imaging of Disease Activity in Atherosclerosis.

Aims The pathophysiology of aortic stenosis shares many similarities with atherosclerosis and skeletal bone formation. Using non-invasive imaging, we compared aortic valve calcification and inflammation activity with that measured in atherosclerosis and bone.

Methods and results Positron emission and computed tomography was performed using 18F-sodium fluoride (18F-NaF, calcification) and 18F-fluorodeoxyglucose (18F-FDG, inflammation) in 101 patients with calcific aortic valve disease (81 aortic stenosis and 20 aortic sclerosis). Calcium scores and positron emission tomography tracer activity (tissue-to-background ratio; TBR) were measured in the aortic valve, coronary arteries, thoracic aorta, and bone. Over 90% of the cohort had coexistent calcific atheroma, yet correlations between calcium scores were weak or absent (valve vs. aorta r 2 = 0.015, P = 0.222; valve vs. coronaries r 2 = 0.039, P = 0.049) as were associations between calcium scores and bone mineral density (BMD vs. valve r 2 = 0.000, P = 0.766; vs. aorta r 2 = 0.052, P = 0.025; vs. coronaries r 2 = 0.016, P = 0.210). 18F-NaF activity in the valve was 28% higher than in the aorta (TBR: 2.66 ± 0.84 vs . 2.11 ± 0.31, respectively, P < 0.001) and correlated more strongly with the severity of aortic stenosis ( r 2 = 0.419, P < 0.001) than 18F-NaF activity outwith the valve (valve vs. aorta r 2 = 0.167, P < 0.001; valve vs. coronary arteries r 2 = 0.174, P < 0.001; valve vs. bone r 2 = 0.001, P = 0.806). In contrast, 18F-FDG activity was lower in the aortic valve than the aortic atheroma (TBR: 1.56 ± 0.21 vs . 1.81 ± 0.24, respectively, P < 0.001) and more closely associated with uptake outwith the valve (valve vs. aorta r 2 = 0.327, P < 0.001).

Conclusion In patients with aortic stenosis, disease activity appears to be determined by local calcific processes within the valve that are distinct from atherosclerosis and skeletal bone metabolism.

Trial Registration: ClinicalTrials.gov number: [NCT01358513][1]

 [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT01358513&atom=%2Fehj%2F34%2F21%2F1567.atom

Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

Dr Vesey and the study were funded by program grants from the British Heart Foundation (PG12/8/29371) and Chest Heart and Stroke Scotland (R13/A147). Dr Jenkins, Vesey, Dweck, and Newby are supported by the British Heart Foundation (FS/14/78/31020, CH/09/002) and the Wellcome Trust (WT103782AIA). Dr Dweck is the recipient of the Sir Jules Thorn Biomedical Research Award 2015. The Wellcome Trust Clinical Research Facility and the Clinical Research Imaging Centre are supported by National Health Service (NHS) Research Scotland (NRS) through NHS Lothian. Dr Beek is supported by the Scottish Imaging Network—a Platform of Scientific Excellence (SINAPSE). Dr Rudd is part-supported by the National Institute for Health Research Cambridge Biomedical Research Centre, the British Heart Foundation, and the Wellcome Trust.

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Aortic stenosis, atherosclerosis and skeletal bone: is there a common link with calcification and inflammation?

Introduction Combined positron emission tomography (PET) and computed tomography (CT) has the potential to assess both the anatomy and biology of carotid atherosclerosis. We sought to assess whether 18F-fluoride or 18F-fluorodeoxyglucose can identify culprit and high-risk carotid plaque. Methods We performed 18F-fluoride and 18F-fluorodeoxygluose PET/CT in 26 patients following recent stroke/transient ischaemic attack: 18 patients with culprit carotid stenosis awaiting carotid endarterectomy and 8 control patients without culprit carotid atheroma. We compared standardised uptake values (SUVs) in the clinically adjudicated culprit to the contralateral asymptomatic artery, and assessed the relationship between radiotracer uptake and plaque phenotype or predicted cardiovascular risk. Results Carotid 18F-fluoride uptake was increased in clinically adjudicated culprit plaques compared to the asymptomatic contralateral plaques (log10SUVmean 0.29±0.10 versus 0.23±0.11, p=0.001) and compared to control patients (log10SUVmean 0.29±0.10 versus 0.12±0.11, p=0.001). 18F-Fluoride uptake correlated with high-risk plaque features (remodelling index [r=0.53, p=0.003]; plaque burden [r=0.51, p=0.004]) and predicted cardiovascular risk (r=0.65, p=0.002). Consistent with the binding of necrotic tissue, 18F-fluoride bound avidly to regions of cerebral infarction (SUVmean4.8±1.98 versus SUVmean of 0.07±0.02, infarcted versus non-infarcted cerebrum; p Conclusion 18F-Fluoride PET/CT highlights culprit carotid plaque. This has the potential to improve risk-stratification and the selection of those patients who would benefit from surgical intervention.

https://heart.bmj.com/content/heartjnl/104/Suppl_5/A1.1.full.pdf

Greg Sng

Papers

Aortic stenosis, atherosclerosis, and skeletal bone: is there a common link with calcification and inflammation?

18F-Fluoride and 18F-Fluorodeoxyglucose Positron Emission Tomography After Transient Ischemic Attack or Minor Ischemic Stroke: Case-Control Study.

Aortic stenosis, atherosclerosis and skeletal bone: is there a common link with calcification and inflammation?

1 18F-fluoride and 18F-fluorodeoxyglucose positron emission tomography after transient ischaemic attack or minor ischaemic stroke