Aortic valve stenosis progression rate is highly variable among patients and to date remains unpredictable. Evaluation of osteoblastic activity inside aortic valves may help identify patients with fast aortic stenosis progression rates and worse prognoses. Fluoride-18 sodium (FNa) is a clinically approved positron emission tomographic (PET) radiotracer with high and rapid bone uptake. The aim of this study was to test whether FNa accumulates in degenerative aortic valves and can be detected with PET imaging. Five patients with severe aortic stenosis and 10 patients free of aortic valvular calcium on computed tomography underwent PET imaging 40 minutes after the injection of 4 MBq/kg of FNa for oncologic or rheumatologic purposes. Maximal standard uptake values (SUVs) were measured retrospectively in aortic valves using PET imaging. Tissue-to-background ratios were calculated for each patient by dividing the maximal SUV measured in aortic valves by the mean SUV of blood. In patients with severe aortic stenosis, an intense accumulation of FNa was detected in aortic valve region on PET imaging, whereas only low activity was found in patients free of valvular calcification (median maximal SUV 2.6 g/ml/kg [interquartile range (IQR) 2.3 to 3.6] vs 2.0 g/ml/kg [IQR 1.7 to 2.2] and median tissue-to-background ratio 2.2 [IQR 2.0 to 2.7] vs 1.5 [IQR 1.5 to 1.7], respectively, p = 0.008 for both). Intraobserver variability for maximal SUV and tissue-to-background ratio in aortic valves was measured at 0.99 and interobserver variability at 0.98 and 0.97, respectively. In conclusion, in this pilot study, FNa accumulated in patients with severe aortic stenosis and could be quantified on PET imaging with good reproducibility. FNa PET imaging represents a promising imaging modality to evaluate osteoblastic activity inside calcified aortic valves.
Aortic valve stenosis (AS) is the most common cause of valve replacement in Europe and North America and the third leading cause of cardiovascular disease. Degenerative AS is caused by progressive calcification of the aortic valve, leading to hemodynamic stenosis. The formation and progression of valvular calcifications is an active and dynamic process involving multiple pathophysiologic pathways sharing similarities with bone formation. AS progression rate is highly variable among patients and to date remains unpredictable. Evaluation of the intrinsic osteoblastic activity into the aortic valve may help identify patients with fast AS progression rates and worse prognoses. Fluoride-18-fluorine sodium (FNa) is a radiotracer that has high and rapid bone uptake. In this pilot study, we tested whether FNa accumulates in calcified aortic valves and can be detected with positron emission tomographic (PET) imaging.
Methods
Five patients with severe AS confirmed by transthoracic echocardiography were retrospectively identified among 160 patients who underwent whole-body FNa PET/computed tomographic (CT) imaging at Bichat University Hospital for oncologic or rheumatologic purposes from December 2009 to February 2011. Echocardiographic evaluation of AS severity was based on mean gradient and aortic valve area, calculated using the continuity equation as recommended. For comparison, 10 patients free of aortic calcification on CT imaging were randomly selected from the 155 remaining patients. Neither controls nor patients with AS had renal insufficiency (creatinine clearance <60 ml/min) or were taking bisphosphonates.
PET and CT imaging were performed with a hybrid PET/CT system (Discovery 690; GE Medical Systems, Milwaukee, Wisconsin). FNa was injected intravenously at a dose of 4 MBq/kg. Patients were hydrated orally with water. Imaging started with a nonenhanced, low-dose CT study of the whole body (tube voltage 120 kV, tube current 80 mA). Next, PET imaging of the whole body was performed in 3-dimensional mode from the head to the legs, with an acquisition time of 3 minutes per bed position. PET imaging of the aortic valve was performed 40 minutes after the injection of FNa. Low-dose CT imaging was used for correction of attenuation with PET imaging. Transverse PET slices were reconstructed into a 256 × 256 matrix with an iterative 3-dimensional reconstruction algorithm in the system software, giving a voxel size of 2.7 × 2.4 × 3.3 mm. Spatial resolution of the reconstructed PET images was calculated at 5 mm in full width at half maximum. PET, CT, and PET/CT fusion images were evaluated visually and quantitatively using the Advantage workstation of the PET/CT system (GE Medical Systems). Maximal standard uptake values (SUVs) adjusted to body weight were measured using PET imaging in circular regions of interest drawn in the aortic valve region located on corresponding CT axial slices. In addition, tissue-to-background ratios (TBR) were calculated for each patient by dividing the maximal SUV measured in the aortic valve by the mean blood SUV measured in a circular region of interest placed in the right atrium. All studies were analyzed initially and 1 week later by one investigator (F.H.) for intraobserver agreement and by a second reader (S.B.) for interobserver agreement.
Statistical analysis was 2 sided and was conducted using MedCalc software (MedCalc, Mariakerke, Belgium). Data are expressed as median values with interquartile ranges (IQRs; 25th and 75th percentiles), and p values <0.05 were considered significant. Patients with AS and controls were compared using nonparametric Mann-Whitney tests for independent samples. Intraclass correlation coefficients with 95% confidence intervals [CIs] were calculated to test intraobserver and interobserver agreement.
Results
As expected, the 5 patients with severe AS were significantly older than the 10 patients free of aortic calcium (mean age 79 vs 53 years, p = 0.04). All 5 patients had severe AS (mean transaortic gradient 52 mm Hg, mean valve area 0.9 cm 2 ; Table 1 ). All patients with known AS had intense FNa accumulation on PET imaging within the regions with valvular calcifications on corresponding nonenhanced CT images ( Figure 1 ) . In contrast, patients free of aortic valve calcium, as demonstrated by noninjected CT scans, had no significant FNa accumulation in the corresponding region on PET imaging.
| Patient | Age (years) | Gender | Symptoms | Maximal Velocity (m/s) | Mean Aortic Gradient (mm Hg) | Aortic Valve Area (cm 2 ) |
|---|---|---|---|---|---|---|
| 1 | 69 | Male | Heart failure | 4.9 | 58 | 0.8 |
| 2 | 78 | Female | Exertional angina | 4.1 | 42 | 0.8 |
| 3 | 83 | Male | Heart failure | 4.7 | 55 | 0.9 |
| 4 | 84 | Male | Exertional angina | 4.1 | 43 | 0.9 |
| 5 | 83 | Female | Dyspnea and exertional angina | 5.0 | 64 | 1.0 |
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