Optimization and Reproducibility of Aortic Valve 18F-Fluoride Positron Emission Tomography in Patients With Aortic Stenosis

Abstract

Background: 18F-Fluoride positron emission tomography (PET) and computed tomography (CT) can measure disease activity and progression in aortic stenosis. Our objectives were to optimize the methodology, analysis, and scan-rescan reproducibility of aortic valve 18F-fluoride PET-CT imaging.

Methods and results: Fifteen patients with aortic stenosis underwent repeated 18F-fluoride PET-CT. We compared nongated PET and noncontrast CT, with a modified approach that incorporated contrast CT and ECG-gated PET. We explored a range of image analysis techniques, including estimation of blood-pool activity at differing vascular sites and a most diseased segment approach. Contrast-enhanced ECG-gated PET-CT permitted localization of 18F-fluoride uptake to individual valve leaflets. Uptake was most commonly observed at sites of maximal mechanical stress: the leaflet tips and the commissures. Scan-rescan reproducibility was markedly improved using enhanced analysis techniques leading to a reduction in percentage error from ±63% to ±10% (tissue to background ratio MDS mean of 1.55, bias -0.05, limits of agreement -0·20 to +0·11).

Conclusions: Optimized 18F-fluoride PET-CT allows reproducible localization of calcification activity to different regions of the aortic valve leaflet and commonly to areas of increased mechanical stress. This technique holds major promise in improving our understanding of the pathophysiology of aortic stenosis and as a biomarker end point in clinical trials of novel therapies.

Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT02132026.

Keywords: 18F-Fluoride; aortic valve stenosis; calcification; disease progression; echocardiography; positron emission tomography.

Figure 1.

Creation of coregistered en face short-axis positron emission tomography (PET)/computed tomography (CT) images of the aortic valve. First, the CT angiogram is reorientated to get into the approximate plane of the aortic valve by lining up the axial cross hair (purple in this example) using the images in the coronal (A) and sagittal planes (C). This creates an approximate cross-sectional image of the aortic valve in the axial frame (B). Scrolling down in the axial frame, the center of the crosshairs is then placed over the exact point at which the right coronary cusp disappears, identifying the base of that leaflet (D). Similarly, the base of the noncoronary cusp is identified, and orthogonal planes adjusted so that the purple plane goes through the base of both these 2 cusps (D). Finally, the base of the left coronary cusp is found by rotation of the axial crosshairs so that first the cusp comes into view. The image is then slowly rotated in the opposite direction until the point where the leaflet first disappears (the base) is again found (F). This produces an en face image of the valve aligned with the base of all 3 leaflets (G). Adjacent 3-mm slices are then created in that plane and used for subsequent assessment. These slices are fused with the 18F-fluoride PET images (H) and careful coregistration performed in 3 dimensions to ensure accurate alignment between the PET and CT images (I).

Figure 2.

Improved localization of positron emission tomography (PET) signal within the aortic valve and its leaflets. Paired nongated, noncontrast PET/computed tomography (CT) scans (original approach A–C and G–I) and gated, contrast-enhanced PET/CT images (final approach D–E and J–L). Images demonstrate the typical distribution of the tracer uptake within the valve at sites of increased mechanical stress, that is, at the leaflet tips (left: A–F) and at the commissures (right: G–L).

Figure 3.

Measuring blood-pool activity in the brachiocephalic vein and the right atrium. Regions of interest for measuring blood-pool activity in the brachiocephalic vein (top) and right atrium (bottom) are shown in the en face of the valve (left) and coronal (right) planes. Note that the right atrium is a much larger structure allowing for larger regions of interest with less potential for partial volume artifact problems related to poor registration. Tukey plot demonstrates mean standard uptake values (SUV) for 5 contiguous slices from brachiocephalic (blue) and 2 from the right atrium (purple). Note the variation in brachiocephalic vein measurements between those taken most caudally vs those taken most cranially.

Figure 4.

Scan–rescan reproducibility for 18F-fluoride positron emission tomography quantification in the aortic valve with consequent sample size estimates. Bland–Altman plots of scan–rescan reproducibility for tissue to background ratio (TBR)_MDSmean measurements using the original image analysis and acquisition methods (left) and then using final method (right). Percentage error for the final method is less than ±10%. Graph (below) shows the sample size estimates needed to detect differences in means that range from 10% to 30% of the initial scan point estimate. The plot illustrates the sample size required to detect differences in means ranging from 10% to 30% with figures shown for 80%, 90%, and 95% power. In all cases, this assumes that the common SD is 18.75%. MDS indicates most diseased segment.