Edwin J. R. van Beek

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

BACKGROUND The use of non-invasive imaging to identify ruptured or high-risk coronary atherosclerotic plaques would represent a major clinical advance for prevention and treatment of coronary artery disease. We used combined PET and CT to identify ruptured and high-risk atherosclerotic plaques using the radioactive tracers (18)F-sodium fluoride ((18)F-NaF) and (18)F-fluorodeoxyglucose ((18)F-FDG). METHODS In this prospective clinical trial, patients with myocardial infarction (n=40) and stable angina (n=40) underwent (18)F-NaF and (18)F-FDG PET-CT, and invasive coronary angiography. (18)F-NaF uptake was compared with histology in carotid endarterectomy specimens from patients with symptomatic carotid disease, and with intravascular ultrasound in patients with stable angina. The primary endpoint was the comparison of (18)F-fluoride tissue-to-background ratios of culprit and non-culprit coronary plaques of patients with acute myocardial infarction. FINDINGS In 37 (93%) patients with myocardial infarction, the highest coronary (18)F-NaF uptake was seen in the culprit plaque (median maximum tissue-to-background ratio: culprit 1·66 [IQR 1·40-2·25] vs highest non-culprit 1·24 [1·06-1·38], p<0·0001). By contrast, coronary (18)F-FDG uptake was commonly obscured by myocardial uptake and where discernible, there were no differences between culprit and non-culprit plaques (1·71 [1·40-2·13] vs 1·58 [1·28-2·01], p=0·34). Marked (18)F-NaF uptake occurred at the site of all carotid plaque ruptures and was associated with histological evidence of active calcification, macrophage infiltration, apoptosis, and necrosis. 18 (45%) patients with stable angina had plaques with focal (18)F-NaF uptake (maximum tissue-to-background ratio 1·90 [IQR 1·61-2·17]) that were associated with more high-risk features on intravascular ultrasound than those without uptake: positive remodelling (remodelling index 1·12 [1·09-1·19] vs 1·01 [0·94-1·06]; p=0·0004), microcalcification (73% vs 21%, p=0·002), and necrotic core (25% [21-29] vs 18% [14-22], p=0·001). INTERPRETATION (18)F-NaF PET-CT is the first non-invasive imaging method to identify and localise ruptured and high-risk coronary plaque. Future studies are needed to establish whether this method can improve the management and treatment of patients with coronary artery disease. FUNDING Chief Scientist Office Scotland and British Heart Foundation.

Assessment of Valvular Calcification and Inflammation by Positron Emission Tomography in Patients With Aortic Stenosis

Background— The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. Methods and Results— Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r2=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r2=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r2=0.174, P<0.001). Conclusions— Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. Clinical Trial Registration— http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

The PREDICT Study: A Randomized Double-Blind Comparison of Contrast-Induced Nephropathy After Low- or Isoosmolar Contrast Agent Exposure

OBJECTIVE The objective of the PREDICT (patients with renal impairment and diabetes undergoing computed tomography) study was to compare the incidence of contrast-induced nephropathy (CIN) after administration of low-osmolar (iopamidol 370, 796 mOsm/kg) or isoosmolar (iodixanol 320, 290 mOsm/kg) contrast medium in patients with diabetes and chronic kidney disease undergoing CT. SUBJECTS AND METHODS Two hundred sixty-three patients with moderate to severe chronic kidney disease (estimated glomerular filtration rate [GFR] = 20-59 mL/min/1.73 m(2)) and diabetes mellitus were randomized to receive at least 65 mL of iopamidol 370 or iodixanol 320 for a CT procedure. Serum creatinine levels were measured at baseline and 48-72 hours after contrast administration. CIN was defined as an increase in the serum creatinine level after contrast administration of >or= 25% from the baseline level. The incidence of CIN in the total study population and the incidence of CIN in patients at increased risk for CIN were compared using Fishers exact test. RESULTS Two hundred forty-eight patients were included in the CIN analysis: 125 receiving iopamidol 370 and 123 receiving iodixanol 320. Study population demographics were comparable, as was baseline renal function (estimated GFR = 47.6 mL/min/1.73 m(2) for the iopamidol 370 group vs 49.9 mL/min/1.73 m(2) for the iodixanol 320 group; p = 0.16). Increases in the serum creatinine value of >or= 25% occurred in seven patients (5.6%) receiving iopamidol 370 and in six patients (4.9%) receiving iodixanol 320 (95% CI, -4.8% to 6.3%; p = 1.0). The mean serum creatinine change from the baseline level was 0.04 mg/dL in both groups (analysis of covariance, p = 0.80). In patients with a baseline serum creatinine value of >or= 2.0 mg/dL, baseline estimated GFR of <or= 40 mL/min/1.73 m(2), or those receiving > 140 mL of contrast medium, the incidence of CIN was low and comparable between the two study groups (p = 1.0 in all instances). CONCLUSION The incidence of CIN in patients with diabetes and chronic kidney disease receiving IV contrast medium was not significantly different after CT using iopamidol 370 or iodixanol 320.

Prospective Study of Color Duplex Ultrasonography Compared with Contrast Venography in Patients Suspected of Having Deep Venous Thrombosis of the Upper Extremities

Context Venography is the standard test for diagnosing deep venous thrombosis of the upper extremities. It is not an ideal test because it requires intravenous access and contrast media. Ultrasonography is a widely available alternative test, but how feasible and accurate is it? Contribution In 126 consecutive patients with suspected upper-extremity thrombosis, venography and ultrasonography were not feasible in 18% and fewer than 1%, respectively. When venography was used as the reference standard, the likelihood ratio for a positive result on ultrasonography was 4.5 (95% CI, 2.53 to 8.02). The likelihood ratio for a negative result was 0.2 (CI, 0.12 to 5.57). Implications Positive findings on ultrasonography are reasonably accurate for diagnosing deep venous thrombosis of the upper extremities. The Editors The exact incidence of deep venous thrombosis (DVT) of the upper extremities is unknown. A prevalence of 2 cases per 1000 hospital admissions has been reported (1). Deep venous thrombosis of the upper extremities is increasingly recognized as causing high mortality and morbidity, similar to DVT of the leg (2, 3). Deep venous thrombosis of the upper extremities is closely associated with malignant disease and the use of central venous access lines (3-11). Nevertheless, few prospective studies on diagnosis and management of DVT of the upper extremities have been published. Contrast venography is generally considered the reference method for diagnosis of DVT of the upper extremities (2, 3). However, because of its inherent problems, such as availability, use of ionizing radiation, necessity of iodinated contrast media, and technical difficulties in obtaining intravenous access, researchers have searched for more appropriate, noninvasive methods. Ultrasonography is widely available and has been used extensively for diagnosis of DVT of the lower extremities (12-18). However, only a few prospective studies have been done in limited numbers of patients to establish its role in the diagnosis of DVT of the upper extremities (3, 19-22). In addition, ultrasonography is problematic because of the anatomy of the upper extremities. The overlying bony structures and the inability to visualize the central intrathoracic venous system limit the value of compression ultrasonography. Therefore, duplex color ultrasonography has been proposed for diagnosis of DVT of the upper extremities (3, 19-24). We sought to assess the diagnostic accuracy of duplex color ultrasonography compared with contrast venography in patients suspected of having DVT of the upper extremities. Methods Study Sample From August 1996 to March 2001, 126 consecutive outpatients and inpatients with clinically suspected DVT of the upper extremities were referred for diagnostic work-up. Three of these patients were referred twice, and 2 patients were referred three times. Patients were excluded if they were pregnant, were younger than 18 years of age, had renal failure prohibiting contrast venography, had a known allergy to iodinated contrast agents, or were unable to provide informed consent. Informed consent for duplex color ultrasonography and venography was obtained at referral from all but 2 patients, and the Institutional Review Board of the Academic Medical Center, Amsterdam, approved the study. Contrast Venography Contrast venography of the symptomatic extremity was performed by using digital subtraction angiography equipment (Polytron, Siemens, Erlangen, Germany). Standardized protocol consisted of a 30-mL contrast injection in the antecubital vein or, if this was not possible, in a more distal forearm vein in the affected arm. No tourniquet was applied. Patients were studied with the examined arm extended and with little abduction of the upper arm to prevent compression of the axillary vein by soft tissues. Low osmolar nonionic contrast was used at a concentration of 300 mg of iodine per liter (Omnipaque, Nycomed-Amersham, Oslo, Norway). All injections were performed by hand. Digital subtraction images of the brachial, axillary, subclavian, and superior caval veins were obtained at a rate of one frame per second. We defined DVT of the upper extremities as the presence of an intraluminal thrombus or persistent nonfilling of a venous segment in the presence of filling of collateral vessels, as demonstrated by contrast venography. All other findings were considered inadequate for interpretation. Duplex Color Ultrasonography Duplex color ultrasonography of the affected extremity was performed with assessment of the basilic, cephalic, axillary, and subclavian veins. The jugular and innominate veins were not included; because the first is visible only on ultrasonography and the second is visible only on venography, comparison is not possible. After identification of the relevant vessels, a three-step procedure was performed. This involved compression ultrasonography of the venous segments that could be reached, assessment of intravascular thrombus by using color ultrasonography, and flow measurements during respiration to determine the outflow of the venous system by using color Doppler ultrasonography. Patients were asked to perform the Valsalva maneuver to allow assessment of changes in flow pattern. Flow patterns of the unaffected veins in the upper extremities were used only in cases of doubt. All tests were performed by senior residents and staff radiologists who had adequate experience in duplex color ultrasonography, using normal departmental practice. We used three qualified ultrasonography machines that were updated but were not changed during the study (Sonos 2000, Hewlett Packard, Andover, Massachusetts; Aloka 1700 and 2000, Aloka, Tokyo, Japan); probes ranged from 4.5 to 7.5 MHz. Duplex color ultrasonography was considered to demonstrate DVT if it showed noncompressibility of a venous segment, a visible intraluminal thrombus, or an abnormal flow pattern (absent flow or absence of phasic flow pattern indicating outflow obstruction) (3). If none of these findings were present, the results were considered normal. All other findings, lack of visualization, and performance of flow measurements were considered inadequate for interpretation. Study Design We performed a prospective comparative study in consecutive patients with clinically suspected DVT of the upper extremities. All patients underwent duplex color ultrasonography as the first test. Results were reported independently and within 4 hours before performance of the reference method, contrast digital venography. Because we followed departmental routine in our teaching hospital, a variety of qualified residents and staff personnel performed the ultrasonography and venography studies at any time during the day or evening. At all times, the radiologist who performed venography was blinded to the initial results on color duplex ultrasonography. Findings on duplex color ultrasonography were compared with those on contrast venography (the reference method). We also assessed potential factors associated with the cause of DVT of the upper extremities, such as the presence of malignant disease, indwelling catheters, or a hypercoagulable state. Statistical Analysis We calculated diagnostic accuracy (sensitivity and specificity), likelihood ratios (25), and 95% CIs for all findings except indeterminate findings on duplex color ultrasonography (because comparison with contrast venography was not possible). Patient groups in which DVT of the upper extremities was confirmed, excluded, or remained uncertain were compared by using the chi-square test. A P value less than 0.05 indicated statistical significance. Results During the inclusion period, 126 patients were eligible for study enrollment. A total of 27 patients was excluded from the analysis. Contrast venography could not be performed in 16 patients because of medical or technical reasons (failure to obtain venous access, n = 10; renal failure, n = 3; pregnancy, n = 2; and iodinated contrast allergy, n = 1). Another 5 patients were excluded because of logistic reasons, and 2 patients declined to provide informed consent. Therefore, venography could not be performed in 23 of 126 patients (18%). In 1 patient, duplex color ultrasonography was not performed because of logistic reasons. Finally, results of duplex color ultrasonography were indeterminate in 3 patients, resulting in a conclusive rate of 98%. A flow diagram of patients is provided in Figure 1. Figure 1. Flow of patients through the study. A total of 99 patients was available for evaluation after undergoing both duplex color ultrasonography and contrast venography. Forty-four patients were men, and 55 were women; the mean age of all patients was 54 years (range, 18 to 92 years). Deep venous thrombosis was demonstrated by contrast venography in 44 patients (44%). The distribution of thrombi in the veins of the right or left upper extremity on venography is shown in Figure 2. Eight patients had primary thrombosis of unknown cause, while an underlying cause could be shown in 36 patients (Table 1). Malignant disease was present in 63% of patients with proven DVT of the upper extremities and in 19 of 55 patients (35%) in whom DVT was excluded (P < 0.01). Figure 2. Distribution of 29 thrombi in the right upper-extremity veins and 33 thrombi in the left upper-extremity veins on digital subtraction venography. Table 1. Identified Causes of Proven Deep Venous Thrombosis of the Upper Extremities in 44 Patients Results on duplex color ultrasonography were compared with results on contrast venography (Table 2). Eight studies were false negative and 10 were false positive, resulting in a sensitivity and specificity of 82% (95% CI, 70% to 93%) and 82% (CI, 72% to 92%), respectively. The likelihood ratio was 4.5 (CI, 2.53 to 8.02) for a true-positive test result and 0.22 (CI, 0.12 to 0.42) for a true-negative test result. Table 2. Duplex Color Ultrasonography Compared with Contrast Venography in 99 Patients

The clinical and genetic features of COPD-asthma overlap syndrome

Individuals with chronic obstructive pulmonary disease (COPD) and asthma are an important but poorly characterised group. The genetic determinants of COPD and asthma overlap have not been studied. The aim of this study was to identify clinical features and genetic risk factors for COPD and asthma overlap. Subjects were current or former smoking non-Hispanic whites or African–Americans with COPD. Overlap subjects reported a history of physician-diagnosed asthma before the age of 40 years. We compared clinical and radiographic features between COPD and overlap subjects. We performed genome-wide association studies (GWAS) in the non-Hispanic whites and African–American populations, and combined these results in a meta-analysis. More females and African–Americans reported a history of asthma. Overlap subjects had more severe and more frequent respiratory exacerbations, less emphysema and greater airway wall thickness compared to subjects with COPD alone. The non-Hispanic white GWAS identified single nucleotide polymorphisms in the genes CSMD1 (rs11779254, p=1.57×10−6) and SOX5 (rs59569785, p=1.61×10−6) and the meta-analysis identified single nucleotide polymorphisms in the gene GPR65 (rs6574978, p=1.18×10−7) associated with COPD and asthma overlap. Overlap subjects have more exacerbations, less emphysema and more airway disease for any degree of lung function impairment compared to COPD alone. We identified novel genetic variants associated with this syndrome. COPD and asthma overlap is an important syndrome and may require distinct clinical management. We identified distinct clinical features and possible genetic risk factors for subjects with both COPD and asthma http://ow.ly/uWWBc

The clinical course of patients with suspected pulmonary embolism.

BACKGROUND The outcome of patients with suspected pulmonary embolism is known to a limited extent only. OBJECTIVE To address this limited knowledge in a cohort in whom pulmonary embolism was proved or ruled out. METHODS Consecutive patients with clinically suspected pulmonary embolism underwent lung scintigraphy and angiography if required. Pulmonary embolism was excluded by normal results of a lung scan or angiogram, and, if so, anticoagulant therapy was withheld. Pulmonary embolism was proved with a high-probability perfusion-ventilation lung scan or a confirmatory angiogram if a nondiagnostic lung scan was obtained. These patients were treated with heparin intravenously and anticoagulants orally on a long-term basis. All patients were followed up for 6 months, with a special focus on recurrent thromboembolism, bleeding complications, and mortality. RESULTS A total of 487 consecutive inpatients and outpatients were included. Pulmonary embolism was excluded or proved in 243 and 193 patients, respectively. In 51 patients a definite diagnosis could not be established. The overall prevalence of pulmonary embolism was 39%. In patients in whom pulmonary embolism was proved, excluded, or uncertain, recurrent venous thromboembolism was observed in 2.6%, 0.9%, and 2%, respectively. Serious bleeding complications occurred in 7 patients (3.3%; 95% confidence interval [CI], 1.8%-6.3%), 2 cases of which were fatal. The total mortality after 6 months in patients with proved or excluded pulmonary embolism was 17% (95% CI, 12%-23%) and 11% (95% CI, 7%-15%), respectively. Death was related to (recurrent) pulmonary embolism in 5% and 0% of these cases, respectively. CONCLUSIONS During a 6-month period, recurrent pulmonary embolism occurred in approximately 5 patients (2.5%) who were treated for a previous episode. Fatal bleeding complications attributable to the use of anticoagulants were encountered in 1%. The mortality among patients with suspected pulmonary embolism was considerable. However, most deaths were unrelated to pulmonary embolism, but were the result of serious underlying illnesses.

A combined pulmonary -radiology workshop for visual evaluation of COPD: study design, chest CT findings and concordance with quantitative evaluation

Abstract The purposes of this study were: to describe chest CT findings in normal non-smoking controls and cigarette smokers with and without COPD; to compare the prevalence of CT abnormalities with severity of COPD; and to evaluate concordance between visual and quantitative chest CT (QCT) scoring. Methods: Volumetric inspiratory and expiratory CT scans of 294 subjects, including normal non-smokers, smokers without COPD, and smokers with GOLD Stage I-IV COPD, were scored at a multi-reader workshop using a standardized worksheet. There were 58 observers (33 pulmonologists, 25 radiologists); each scan was scored by 9–11 observers. Interobserver agreement was calculated using kappa statistic. Median score of visual observations was compared with QCT measurements. Results: Interobserver agreement was moderate for the presence or absence of emphysema and for the presence of panlobular emphysema; fair for the presence of centrilobular, paraseptal, and bullous emphysema subtypes and for the presence of bronchial wall thickening; and poor for gas trapping, centrilobular nodularity, mosaic attenuation, and bronchial dilation. Agreement was similar for radiologists and pulmonologists. The prevalence on CT readings of most abnormalities (e.g. emphysema, bronchial wall thickening, mosaic attenuation, expiratory gas trapping) increased significantly with greater COPD severity, while the prevalence of centrilobular nodularity decreased. Concordances between visual scoring and quantitative scoring of emphysema, gas trapping and airway wall thickening were 75%, 87% and 65%, respectively. Conclusions: Despite substantial inter-observer variation, visual assessment of chest CT scans in cigarette smokers provides information regarding lung disease severity; visual scoring may be complementary to quantitative evaluation.

Association between Functional Small Airway Disease and FEV1 Decline in Chronic Obstructive Pulmonary Disease.

RATIONALE The small conducting airways are the major site of airflow obstruction in chronic obstructive pulmonary disease and may precede emphysema development. OBJECTIVES We hypothesized a novel computed tomography (CT) biomarker of small airway disease predicts FEV1 decline. METHODS We analyzed 1,508 current and former smokers from COPDGene with linear regression to assess predictors of change in FEV1 (ml/yr) over 5 years. Separate models for subjects without and with airflow obstruction were generated using baseline clinical and physiologic predictors in addition to two novel CT metrics created by parametric response mapping (PRM), a technique pairing inspiratory and expiratory CT images to define emphysema (PRM(emph)) and functional small airways disease (PRM(fSAD)), a measure of nonemphysematous air trapping. MEASUREMENTS AND MAIN RESULTS Mean (SD) rate of FEV1 decline in ml/yr for GOLD (Global Initiative for Chronic Obstructive Lung Disease) 0-4 was as follows: 41.8 (47.7), 53.8 (57.1), 45.6 (61.1), 31.6 (43.6), and 5.1 (35.8), respectively (trend test for grades 1-4; P < 0.001). In multivariable linear regression, for participants without airflow obstruction, PRM(fSAD) but not PRM(emph) was associated with FEV1 decline (P < 0.001). In GOLD 1-4 participants, both PRM(fSAD) and PRM(emph) were associated with FEV1 decline (P < 0.001 and P = 0.001, respectively). Based on the model, the proportional contribution of the two CT metrics to FEV1 decline, relative to each other, was 87% versus 13% and 68% versus 32% for PRM(fSAD) and PRM(emph) in GOLD 1/2 and 3/4, respectively. CONCLUSIONS CT-assessed functional small airway disease and emphysema are associated with FEV1 decline, but the association with functional small airway disease has greatest importance in mild-to-moderate stage chronic obstructive pulmonary disease where the rate of FEV1 decline is the greatest. Clinical trial registered with www.clinicaltrials.gov (NCT 00608764).

18F-Sodium Fluoride Uptake Is a Marker of Active Calcification and Disease Progression in Patients With Aortic Stenosis

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: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

18F-NaF Uptake Is a Marker of Active Calcification and Disease Progression in Patients with Aortic Stenosis

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: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.