18F-sodium Fluoride Positron Emission Tomography Research Articles

Effect of Denosumab or Alendronate on Vascular Calcification: Secondary Analysis of SALTIRE2 Randomized Controlled Trial.

Patients with osteoporosis demonstrate increased vascular calcification but the effect of osteoporosis treatments on vascular calcification remains unclear. The present study aimed to examine whether coronary or aortic calcification are influenced by denosumab and alendronic acid treatment. In a double-blind randomized controlled SALTIRE2 (Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis) trial, patients with aortic stenosis were randomized 2:1:2:1 to denosumab, placebo injection, alendronic acid, or placebo capsule. Participants underwent serial imaging with computed tomography and 18F-sodium fluoride positron emission tomography for the assessment of vascular calcium burden and calcification activity, respectively. We report the prespecified secondary analyses of 24-month change in coronary calcium score, and 12-month changes in thoracic aorta calcium score, coronary and aortic 18F-sodium fluoride activity. One hundred fifty patients with aortic stenosis (72±8 years; 21% female) were randomized to denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25). There were no differences in change in coronary calcium scores between placebo (16 [-64 to 148] Agatston units) and either denosumab (94 [0-212] Agatston units, P=0.24) or alendronic acid (34 [-62 to 134], P=0.99). There were no differences in change in thoracic aorta calcium scores between placebo (132 [22-512] Agatston units) and either denosumab (118 [11-340], P=0.75) or alendronic acid (116 [26-498] Agatston units, P=0.62). There were no differences in changes in coronary or aortic 18F-sodium fluoride activity between treatment groups. Neither alendronic acid nor denosumab are associated with changes in the activity or progression of coronary or aortic calcification. Osteoporosis treatments do not appear to have major impact on vascular calcification of atherosclerosis. https://www.clinicaltrials.gov; Unique identifier: NCT02132026.

Using accelerometers to identify a high risk of catastrophic musculoskeletal injury in three racing Thoroughbreds.

To describe the process whereby the screening of racing Thoroughbreds with accelerometer-based inertial measurement unit (IMU) sensors followed by clinical evaluation and advanced imaging identified potentially catastrophic musculoskeletal injuries in 3 horses. 3 Thoroughbred racehorses. All cases demonstrated an abnormal stride pattern either during racing (cases 1 and 2) or while breezing (case 3) and were identified as being at very high risk of catastrophic musculoskeletal injury by an algorithm derived from IMU sensor files from > 20,000 horses' race starts. Veterinary examination and 18F-sodium fluoride (18F-NaF) positron emission tomography were performed within 10 days of the respective race or breeze in each of the cases. The intensity and location of the 18F-NaF uptake in the condyles of the third metacarpal bone in cases 1 and 2 identified them as at potential increased risk of condylar fracture. The pattern and intensity of the 18F-NaF uptake in case 3 indicated that the third carpal bone was likely responsible for the horse's lameness, with an impending slab fracture subsequently identified on radiographs. Following periods of convalescence, cases 1 and 2 returned to racing and were identified by the sensor system as no longer being at high risk of catastrophic musculoskeletal injury. Case 3 returned to training but has yet to return to racing. When worn by Thoroughbreds while racing or breezing, these IMU sensors can identify horses at high risk of catastrophic musculoskeletal injury, allowing for veterinary intervention and the potential avoidance of such injuries.

Dissecting the heterogeneity of craniofacial lesions in patients with fibrous dysplasia/McCune–Albright Syndrome

Fibrous dysplasia/McCune–Albright Syndrome (FD/MAS) frequently involves the craniofacial skeleton. Craniofacial fibrous dysplasia lesions exhibit diverse imaging characteristics on multimodality evaluation, utilizing radiographs, computed tomography (CT), magnetic resonance imaging (MRI), and 18F-sodium fluoride positron emission tomography (18F-NaF PET). A multimodal imaging classification of craniofacial fibrous dysplasia lesions may offer clinical insights into the types of lesions that are (1) prone to progression, (2) amenable to intervention (i.e., pharmacological or surgical), or (3) associated with symptoms such as pain. In this prospective, preliminary single site study of 15 patients with FD/MAS, the heterogeneity of craniofacial lesions (N = 35) was assessed using a combination of 18F-NaF PET, MRI, and CT. A k-means clustering algorithm was used to categorize lesions based on imaging characteristics. Clustering analysis revealed three types of lesion based on the magnitude of the regional 18F-NaF standardized uptake values (SUV), signal intensities on T1-weighted and fluid-sensitive sequences, and appearance on CT (lucent, sclerotic, and/or ground glass). This preliminary study provides a foundation for future longitudinal natural history or treatment studies, where the prognostic value of baseline craniofacial fibrous dysplasia imaging characteristics and clinical symptomatology can be further evaluated.

Sex differences in coronary atherosclerotic plaque activity using 18F-sodium fluoride positron emission tomography.

There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.

Carotid atherosclerotic plaque microcalcification is independently associated with recurrent neurovascular events: A pilot study.

Microcalcification and macrocalcification are critical processes in atherosclerotic plaque progression, though how these processes relate to the risk of stroke recurrence in symptomatic carotid atherosclerosis is poorly understood. We performed a post hoc analysis of data from the ICARUSS (Imaging Carotid Atherosclerosis in the Recovery and Understanding of Stroke Severity) study, where individuals with acute ischemic stroke originating from ipsilateral carotid stenosis of ⩾ 50% underwent 18F-sodium fluoride positron emission tomography (NaF-PET) to measure microcalcification. Tracer uptake was quantified using maximum tissue-to-background ratio (TBRmax). Macrocalcification was measured on computed tomography (CT) using Agatston scoring. Patients were followed up for 6 months for recurrent ipsilateral neurovascular events. Five (27.8%) of 18 individuals had a recurrent ischemic stroke or transient ischemic attack. Ipsilateral carotid plaque NaF uptake at baseline was higher in those with recurrent events compared to those without, and this association remained after adjustment for other vascular risk factors (adjusted odds ratio (aOR) = 1.24, 1.03-1.50). Macrocalcification score in the symptomatic artery was also significantly independently associated with ipsilateral recurrence, but the effect size was relatively smaller (aOR = 1.12, 1.06-1.17 for each 100 unit increase). Our findings indicate that microcalcification in symptomatic carotid plaques is independently associated with ipsilateral ischemic stroke recurrence. Furthermore, differences in the extent of active microcalcification in macrocalcified plaques may help explain variation in the relationship between calcified carotid plaques and stroke recurrence reported in the literature. Our pilot study indicates that evaluation of carotid artery microcalcification using NaF-PET may be a useful method for risk-stratification of carotid atherosclerosis, though our findings require confirmation in larger cohorts.

Temporal changes in biomarker levels and their association with the early degeneration stage of transcatheter aortic valves in 18F-fluorodeoxyglucose and 18F-sodium fluoride positron emission tomography studies

Temporal changes in biomarker levels and their association with the early degeneration stage of transcatheter aortic valves in 18F-fluorodeoxyglucose and 18F-sodium fluoride positron emission tomography studies

18F-fluorodeoxyglucose and 18F-sodium fluoride positron emission tomography imaging in assessing early stages of aortic valve degeneration after transcatheter aortic valve implantation.

Transcatheter aortic valve implantation (TAVI) is a standard treatment for severe aortic stenosis, primarily in elderly patients. With an increasing number of procedures and younger patients, understanding the valve degeneration and its risk factors becomes crucial. We aimed to utilize 18F‑sodium fluoride (18F‑NaF) and 18F‑fluorodeoxyglucose (18F‑FDG) positron emission tomography/computed tomography (PET/CT) to evaluate early TAVI valve degeneration. In this prospective study with a prespecified follow‑up protocol, 71 TAVI patients underwent baseline transthoracic and transesophageal echocardiography, and PET/CT with 18F‑NaF and 18F‑FDG. Of these, 31 patients completed 24‑month control examinations, while the others were lost to mortality and the COVID‑19 pandemic. We measured PET tracer activity and compared 18F‑NaF and 18F‑FDG PET/CT uptake at baseline and 24‑month follow‑up. PET/CT and echocardiography data were analyzed for 31 of the 71 enrolled TAVI patients at a median age of 84 years (interquartile range, 80-86). After TAVI, an improvement in the valve function was observed. During follow‑up, the valve function remained stable. PET/CT demonstrated an increase in 18F‑FDG maximal uptake in the inner (tissue‑to‑background ratio, P = 0.009) and outer (P = 0.01) sides of the TAVI valve stent, but no difference in 18F‑NaF maximal activity (inner, P = 0.17; outer, P = 0.57). Twenty‑four months post‑TAVI, an increase in 18F‑FDG uptake, indicative of inflammation, was observed in the valve, while the uptake of the calcification marker (18F‑NaF) remained stable. Theseobservations might suggest early stages of TAVI valve degeneration, although further investigation is required to confirm this interpretation.

Bioprosthetic aortic valve degeneration evaluated by 18F-fluoride PET-TC

Abstract Background Implantation of bioprosthetic aortic valves (BPHV) is increasing owing to the aging population and the emergence of transcatheter aortic valve implantation. Along with the increase in life expectancy, BPHV degeneration is therefore becoming an increasing problem. 18F-fluoride positron emission tomography (PET) has emerged as a method that could identify early subclinical BPHV degeneration. Purpose We aimed to compare early PET parameters of fluorid uptake with echocardiographic hemodynamic parameters at three years after the implantation of a bioprosthetic aortic valve. Methods Sub-analysis of the ANTIPRO clinical trial. Patients undergoing aortic valve replacement (AVR) for porcine bioprosthesis were recruited at two surgical centers between 01/01/2019 and 02/13/2020, and were randomized in two groups (acetylsalicylic acid (ASA) vs ASA and oral anticoagulation for 3 months). Clinical and echocardiographic controls were performed one year and three years after AVR. Bioprosthetic valve deterioration (BVD) was defined according to the Valve Academic Research Consortium 3. 43 subjects were randomly selected from the whole cohort to undergo 18F-sodium fluoride PET with CT angiography (PET-CT) at follow-up. 18F-fluoride uptake in the valve (SUVavV) and right atrium (SUVavA) was measured, creating the SUVavV/SUVavA ratio or target-to-background ratio (TBR). PET findings were categorized as "high uptake" if TBR &amp;gt; 1.3 and "low uptake" if TBR ≤1.3. TBR was compared with the mean and maximum gradients at three years. Survival between high and low uptake groups was calculated using Kaplan-Meier and compared with log-rank test. The project was approved by the national ethics committee and patients consented the procedure. Results 18F-sodium fluoride PET-CT was performed on 43 subjects, with a mean time of 22.7±8.4 months after AVR. The echocardiogram at three years was performed in a mean time of 39.9±3.0 months after AVR. Mean time between PET-CT and echocardiogram was 17.2±9.9 months. The mean TBR was 1.25±0.30. Low uptake was found in 27 patients (62.8%) and high uptake in 15 patients (34.9%). Uptake could not be quantified in one patient due to technical problems. Baseline characteristics were similar between both groups (Table 1). Mean gradient at three years was 19.6±10.3 and peak gradient 33.7±16.7. Mean gradient was similar between the high uptake and low uptake groups (17.5±11.7 vs 21.6±9.3 p=0.296). Peak gradient was also similar between the high uptake and low uptake groups (30.6±18.5 vs 36.3±15.6 p=0.362). Five patients experienced BVD, of which 4 had low uptake and 1 had high uptake (p=0.523). Survival analysis did not demonstrate statistically different survival rates between the high uptake and low uptake groups (Figure 1). Conclusion Fluorid uptake with early PET after AVR was not associated with trans-prosthetic gradients nor BVD after a mean of 17 months from the PET scan.Table 1:Baseline characteristicsFigure 1:Kaplan-Meier survival curve

Aortic valve perivascular adipose tissue computed tomography attenuation in patients with aortic stenosis

ObjectiveAortic stenosis (AS) shares pathophysiological similarities with atherosclerosis including active inflammation. CT attenuation of perivascular adipose tissue provides a measure of vascular inflammation that is linked to prognosis and has...

Comparison of 18F-sodium fluoride positron emission tomography and computed tomography for imaging of the fetlock in 25 nonracehorses.

18F-sodium fluoride (18F-NaF) positron emission tomography (PET) has been validated as a useful imaging technique in the racehorse fetlock. The use of 18F-NaF PET in the nonracehorse fetlock has not been reported. To describe 18F-NaF PET findings in nonracehorse fetlocks, to compare with computed tomography (CT) findings and to compare PET findings between horses with and without fetlock pain. Retrospective observational study. All horses undergoing 18F-NaF PET and CT imaging of the fetlock between October 2016 and March 2021 were included in the study. Medical records were reviewed for associated lameness information. Thirty-six fetlocks (33 front and 3 hind) from 25 horses were included. The interobserver agreement for PET [0.62 (95% confidence interval [CI] 0.59-0.65)] was higher than for CT [0.47 (95% CI 0.43-0.51)]. Increased 18F-NaF uptake was most common in the medial subchondral bone of the proximal phalanx (23/36), the dorsomedial (20/36) and dorsosagittal (16/36) metacarpal/metatarsal distal subchondral bone, whereas sclerosis was identified on CT in these areas in 22 of 36 (p > 0.9), 33 of 36 (p = 0.001) and 23 of 36 (p = 0.15), respectively. Significant correlations were found between PET grades and both subchondral sclerosis and resorption CT grades (p < 0.001, Spearman r = 0.19 and 0.21, respectively). Abnormal 18F-NaF uptake in the proximal sesamoid bones (PSBs) was identified in 12 of 36 of the fetlocks, which was more common than CT abnormalities (3/36, p = 0.02). Periarticular increased uptake was seen in 7 of 36 fetlocks, whereas osteophytosis was recognised on CT in 20 of 36 (p = 0.1). Maximal standardised uptake values (SUVmax) were significantly higher in painful than in nonpainful fetlocks (22.0 and 11.9, respectively, p = 0.038). Retrospective study and limited sample size. Overall PET and CT findings follow a similar distribution in their location. PET identified more abnormalities in the PSBs than CT. SUVmax is a pertinent factor to take into consideration for the assessment of the clinical significance of findings.

Quantitative Analysis of Serial Positron Emission Tomography Imaging in Men with Metastatic Castration-resistant Prostate Cancer Treated with Enzalutamide

BackgroundThe emergence of positron emission tomography (PET) in prostate cancer is impacting clinical practice, but little is known about PET imaging as a tool to determine treatment failure in metastatic castration-resistant prostate cancer (mCRPC). ObjectiveTo evaluate PET imaging dynamics in mCRPC patients on enzalutamide with stable computed tomography (CT) and technetium-99m (Tc99) bone scans. Design, setting, and participantsAll patients were on treatment with enzalutamide for first-line mCRPC in a clinical trial at the National Cancer Institute (Bethesda, MD, USA). A volunteer sample had serial 18F-sodium fluoride (NaF) PET in parallel with CT and Tc99. Regions of interest (ROIs) on NaF were analyzed quantitatively for response. InterventionPatients were randomized to enzalutamide with/without a cancer immunotherapy, Prostvac. Outcome measurements and statistical analysisA post hoc, descriptive analysis was performed comparing the changes seen on CT and Tc99 as per RECIST 1.1 with NaF PET scans including the use of a quantitative analysis. Results and limitationsEighteen mCRPC patients had 67 NaF scans. A total of 233 ROIs resolved after treatment, 52 (22%) of which eventually retuned while on therapy. In all, 394 new ROIs were seen, but 112(28%) resolved subsequently. Of 18 patients, 14 had new ROIs that ultimately resolved after appearing. Many patients experienced progression in a minority of lesions, and one patient with radiation intervention to oligoprogression had a remarkable response. This study is limited by its small number of patients and post hoc nature. ConclusionsThese data highlight the dynamic nature of NaF PET in mCRPC patients treated with enzalutamide, where not all new findings were ultimately related to disease progression. This analysis also provides a potential strategy to identify and intervene in oligoprogression in prostate cancer. Patient summaryIn this small analysis of patients with prostate cancer on enzalutamide, changes on 18F-sodium fluoride positron emission tomography (PET) imaging were not always associated with treatment failure. Caution may be indicated when using PET imaging to determine whether new therapy is needed.

Positron emission tomography assessment of metacarpal/metatarsal condylar fractures post surgical repair: Prospective study in 14 racehorses.

To assess 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) findings associated with metacarpal/metatarsal condylar fractures at the time of fracture repair and through healing. Prospective descriptive study. Fourteen Thoroughbred racehorses. 18F-NaF PET was performed within 4 days of surgical metacarpal/metatarsal condylar fracture repair, on both the injured and contralateral limb. Follow-up PET scans were offered at 3- and 5-months post fracture repair. Areas of abnormal uptake were assessed using a previously validated grading system. Eight fractures were located in the parasagittal groove (PSG) (six lateral and two medial) and six fractures were located abaxial to the PSG (non-PSG) through the palmar/plantar condyle (all lateral). All horses in the latter group had uptake in the lateral palmar condyle of the contralateral limb suggestive of stress remodeling. Three horses with PSG fractures had uptake in a similar location in the contralateral limb. Horses with lateral condylar fracture only presented minimal or mild uptake in the medial condyle, which is considered atypical in the front limbs for horses in full training. Four horses developed periarticular uptake in the postoperative period suggestive of degenerative joint disease, three of these horses had persistent uptake at the fracture site. These four horses did not return to racing successfully. The findings of this study provide evidence of pre-existing lesions and specific uptake patterns in racehorses suffering from metacarpal/metatarsal condylar fractures. PET has a possible role in the prevention, diagnosis, and postoperative monitoring of metacarpal/metatarsal condylar fractures in racehorses.

18F-sodium fluoride positron emission tomography provides pertinent additional information to computed tomography for assessment and management of tarsal pain in horses.

To assess the value of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) for imaging the tarsus and proximal metatarsus and compare it with CT and lameness evaluation. 25 horses with lameness localized to the tarsal and proximal metatarsal regions that underwent 18F-NaF PET/CT between 2016 and 2021. 18F-NaF PET and CT images were retrospectively independently evaluated by 3 observers. Standardized uptake values (SUV) were used to characterize 18F-NaF uptake. Correlation between PET and CT findings with subjective and objective maximum (Max-D) and minimum pelvic height lameness data was estimated. The inter-observer Kappa-weighted value (κ) was higher for PET (κ = 0.66) than CT (κ = 0.6). CT and PET scores were fairly correlated (R = 0.49; P < 0.05). PET SUVratio (SUV of the main lesion/SUV talus) had the highest correlation with Max-D (R = 0.71; P < .05). PET and CT scores for the plantar region were significantly higher in Quarter Horses (P < .05) and showed consistently higher correlation with objective lameness data (CT plantar grade - Max-D [R = 0.6; P < .05], PET plantar grade - Max-D [R = 0.47; P = .04]) than other regions of the distal tarsal joints. Three Warmbloods presented marked uptake at the medial cochlea of the distal tibia. PET had a moderate correlation with CT for assessment of tarsal lesions. The degree of PET uptake can help differentiate active versus inactive lesions. Specific location of the uptake is important in determining clinical relevance.

Coronary Atherosclerotic Plaque Activity and Future Coronary Events

Recurrent coronary events in patients with recent myocardial infarction remain a major clinical problem. Noninvasive measures of coronary atherosclerotic disease activity have the potential to identify individuals at greatest risk. To assess whether coronary atherosclerotic plaque activity as assessed by noninvasive imaging is associated with recurrent coronary events in patients with myocardial infarction. This prospective, longitudinal, international multicenter cohort study recruited participants aged 50 years or older with multivessel coronary artery disease and recent (within 21 days) myocardial infarction between September 2015 and February 2020, with a minimum 2 years' follow-up. Coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography. Total coronary atherosclerotic plaque activity was assessed by 18F-sodium fluoride uptake. The primary end point was cardiac death or nonfatal myocardial infarction but was expanded during study conduct to include unscheduled coronary revascularization due to lower than anticipated primary event rates. Among 2684 patients screened, 995 were eligible, 712 attended for imaging, and 704 completed an interpretable scan and comprised the study population. The mean (SD) age of participants was 63.8 (8.2) years, and most were male (601 [85%]). Total coronary atherosclerotic plaque activity was identified in 421 participants (60%). After a median follow-up of 4 years (IQR, 3-5 years), 141 participants (20%) experienced the primary end point: 9 had cardiac death, 49 had nonfatal myocardial infarction, and 83 had unscheduled coronary revascularizations. Increased coronary plaque activity was not associated with the primary end point (hazard ratio [HR], 1.25; 95% CI, 0.89-1.76; P = .20) or unscheduled revascularization (HR, 0.98; 95% CI, 0.64-1.49; P = .91) but was associated with the secondary end point of cardiac death or nonfatal myocardial infarction (47 of 421 patients with high plaque activity [11.2%] vs 19 of 283 with low plaque activity [6.7%]; HR, 1.82; 95% CI, 1.07-3.10; P = .03) and all-cause mortality (30 of 421 patients with high plaque activity [7.1%] vs 9 of 283 with low plaque activity [3.2%]; HR, 2.43; 95% CI, 1.15-5.12; P = .02). After adjustment for differences in baseline clinical characteristics, coronary angiography findings, and Global Registry of Acute Coronary Events score, high coronary plaque activity was associated with cardiac death or nonfatal myocardial infarction (HR, 1.76; 95% CI, 1.00-3.10; P = .05) but not with all-cause mortality (HR, 2.01; 95% CI, 0.90-4.49; P = .09). In this cohort study of patients with recent myocardial infarction, coronary atherosclerotic plaque activity was not associated with the primary composite end point. The findings suggest that risk of cardiovascular death or myocardial infarction in patients with elevated plaque activity warrants further research to explore its incremental prognostic implications.

#6643 MOLECULAR PATHWAYS ASSOCIATED WITH VASCULAR CALCIFICATIONS IN CHILDREN WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Patients with advanced stages of chronic disease (CKD) suffer from 30-times higher risk of cardiovascular disease (CVD) as compared to the general population, vascular calcifications are prevalent. Underlying molecular mechanisms are only partly understood. Children are devoid of life-style and aging related CVD risk factors and therefore allow for a highly sensitive and specific analyses of CKD induced pathomechanisms. Method Arteriolar tissues of 55 children with normal renal function and 29 children with CKD5 (median age 9.2 years) underwent digital histomorphometry, calcium deposits were assessed by Von Kossa staining and 18F-sodium fluoride positron emission tomography (18F-NaF PET). Gene set enrichment (GSEA) and Ingenuity pathway analysis were performed on multi-omics data sets obtained from micro-dissected omental arterioles from children with normal renal function and with CKD5 (n = 7/group; age 7.3 ± 3/6.8 ± 3 years). Based on literature review, we established a vascular calcification (VC) pathway library comprising 442 biological processes/molecular functions and extracted linked genes from Gene Ontology database. Key identified mechanisms were validated in independent patient cohorts (n = 32) and controls (n = 20) by quantitative immunostaining. Results Significant arteriolar lumen obliteration was present in CKD5 children (p = 0.001), intima and media thickness were increased (p&amp;lt;0.0001 and p = 0.02). Von Kossa staining was negative, but 18F-NaF PET revealed microcalcifications in children with CKD5. Subendothelial arteriolar inflammatory cells (CD68+ macrophages) were present in CKD5 cohort (p&amp;lt;0.0001 compared to non-CKD controls) and correlated with serum inorganic phosphorus (R2 = 0.18; p = 0.04). GSEA identified top enriched pathways including telomere extension by telomerase and chromatin histone methylation. IPA cross-omics showed suppression of actin cytoskeleton, tight junction signaling, and focal adhesion. VC pathway analysis identified 30/442 pathways related to actin cytoskeleton, Wnt signaling, extracellular matrix (ECM) organization, complement activation, apoptosis, endoplasmic reticulum stress and ossification regulation. Fibronectin-1 (FN1) was identified as Hubgene, involved in ECM regulation. In independent age-matched cohorts, complement factor C3d was higher in CKD5, vascular endothelial growth factor and endothelial cell number/µm endoluminal circumference were reduced. Arteriolar osteoglycin, a protein inducing ectopic bone formation, was increased and correlated with serum PTH (R2 = 0.61; p = 0.01). FN1 was less abundant in arterioles from CKD5 children and negatively correlated with serum creatinine levels (R2 = −0.62; p = 0.02). Conclusion Vascular disease and microcalcifications are present in young children with CKD5. We provide the first comprehensive analysis of the underlying molecular mechanisms associated with the vascular calcifications and identified specific molecular pathomechanisms, of which several represent potential therapeutic targets.

Latent Coronary Plaque Morphology From Computed Tomography Angiography, Molecular Disease Activity on Positron Emission Tomography, and Clinical Outcomes.

Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography and radiomics-based precision coronary plaque phenotyping derived from coronary computed tomography angiography may enhance risk stratification in patients with coronary artery disease. We sought to investigate whether the prognostic information provided by these 2 approaches is complementary in the prediction of myocardial infarction. Patients with known coronary artery disease underwent coronary 18F-sodium fluoride positron emission tomography and coronary computed tomography angiography on a hybrid positron emission tomography/computed tomography scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity. We performed quantitative plaque analysis of coronary computed tomography angiography datasets and extracted 1103 radiomic features for each plaque. Using weighted correlation network analysis, we derived latent morphological features of coronary lesions which were aggregated to patient-level radiomics nomograms to predict myocardial infarction. Among 260 patients with established coronary artery disease (age, 65±9 years; 83% men), 179 (69%) participants showed increased coronary 18F-NaF activity (coronary microcalcification activity>0). Over 53 (40-59) months of follow-up, 18 patients had a myocardial infarction. Using weighted correlation network analysis, we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns in an unsupervised fashion. Following adjustments for calcified, noncalcified, and low-density noncalcified plaque volumes and 18F-NaF coronary microcalcification activity, 4 radiomic features remained independent predictors of myocardial infarction (hazard ratio, 1.46 [95% CI, 1.03-2.08]; P=0.03; hazard ratio, 1.62 [95% CI, 1.04-2.54]; P=0.02; hazard ratio, 1.49 [95% CI, 1.07-2.06]; P=0.01; and hazard ratio, 1.50 (95% CI, 1.05-2.13); P=0.02). In patients with established coronary artery disease, latent coronary plaque morphological features, quantitative plaque volumes, and disease activity on 18F-sodium fluoride positron emission tomography are additive predictors of myocardial infarction.

18F-sodium fluoride positron emission tomography following coronary computed tomography angiography in predicting long-term coronary events: a 5-year follow-up study.

The predictive value of 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) in combination with coronary computed tomography (CT) angiography (CCTA) for future coronary events has attracted interest. We evaluated the potential of 18F-NaF PET/CT following CCTA to predict major coronary events (MACE) during a 5-year follow-up period. Forty patients with coronary atherosclerotic lesions detected on CCTA underwent 18F-NaF PET/CT examination. Each lesion was evaluated for luminal stenosis and high-risk plaque (HRP) with < 30 Hounsfield units and a > 1.1 remodeling index on CCTA. Focal 18F-NaF uptake in each lesion was quantified using the maximum tissue-to-background ratio (TBRmax), and the maximum TBRmax per patient (M-TBRmax) was determined. We followed MACE (cardiac death, acute coronary syndrome, and/or coronary revascularization > 6months after 18F-NaF PET/CT) for 5years. In total, 142 coronary lesions were analyzed. Eleven patients experienced any MACE. Patients with MACE showed a higher M-TBRmax than those without (1.40 ± .19 vs. 1.18 ± .18, P = .0011), and the optimal M-TBRmax cutoff to predict MACE was 1.29. Patients with M-TBRmax of ≥ 1.29 had a higher risk of MACE than those with lower values (P = .012, log-rank test), whereas patients with obstructive stenosis and those with HRP did not. Multivariate Cox proportional analysis adjusted for age, sex, coronary risk factors, and CCTA findings showed that M-TBRmax of ≥ 1.29 remained an independent predictor of 5-year MACE (hazard ratio, 5.4; 95% confidence interval, 1.1-25.4; P = .034). 18F-NaF PET/CT following CCTA provides useful strategies to predict 5-year MACE.

Serum lipoprotein(a) and bioprosthetic aortic valve degeneration.

Bioprosthetic aortic valve degeneration demonstrates pathological similarities to aortic stenosis. Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for incident aortic stenosis and disease progression. The aim of this study is to investigate whether serum Lp(a) concentrations are associated with bioprosthetic aortic valve degeneration. In a post hoc analysis of a prospective multimodality imaging study (NCT02304276), serum Lp(a) concentrations, echocardiography, contrast-enhanced computed tomography (CT) angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) were assessed in patients with bioprosthetic aortic valves. Patients were also followed up for 2 years with serial echocardiography. Serum Lp(a) concentrations [median 19.9 (8.4-76.4) mg/dL] were available in 97 participants (mean age 75 ± 7 years, 54% men). There were no baseline differences across the tertiles of serum Lp(a) concentrations for disease severity assessed by echocardiography [median peak aortic valve velocity: highest tertile 2.5 (2.3-2.9) m/s vs. lower tertiles 2.7 (2.4-3.0) m/s, P = 0.204], or valve degeneration on CT angiography (highest tertile n = 8 vs. lower tertiles n = 12, P = 0.552) and 18F-NaF PET (median tissue-to-background ratio: highest tertile 1.13 (1.05-1.41) vs. lower tertiles 1.17 (1.06-1.53), P = 0.889]. After 2 years of follow-up, there were no differences in annualized change in bioprosthetic hemodynamic progression [change in peak aortic valve velocity: highest tertile [0.0 (-0.1-0.2) m/s/year vs. lower tertiles 0.1 (0.0-0.2) m/s/year, P = 0.528] or the development of structural valve degeneration. Serum lipoprotein(a) concentrations do not appear to be a major determinant or mediator of bioprosthetic aortic valve degeneration.

18F-sodium fluoride positron emission tomography and coronary plaque radiomics derived from computed tomography angiography for prediction of myocardial infarction

Abstract Background Assessments of coronary disease activity with 18F-sodium fluoride positron emission tomography (18F-NaF PET) and radiomics-based precision coronary plaque phenotyping derived from contrast-enhanced computed tomography (CT) have both been shown to enhance risk stratification in patients with coronary artery disease (CAD). To date, no study has investigated whether these two promising methods (which can be obtained during a single imaging session on a hybrid PET/CT scanner) are interchangeable or can provide superior predictive performance when used in combination. Purpose We sought to investigate whether the prognostic information provided by latent morphological radiomic coronary plaque features and assessments of disease activity by 18F-NaF PET are complementary in prediction of myocardial infarction. Methods Patients with known CAD underwent coronary 18F-NaF PET and CT angiography on a hybrid PET/CT scanner. Coronary 18F-NaF uptake was determined by the coronary microcalcification activity (CMA). We performed quantitative plaque analysis of coronary CT angiography datasets. Additionally, coronary plaque segmentations on CT angiography were used to extract 1103 radiomic features. Using weighted correlation network analysis we derived latent morphological features of coronary plaques which were aggregated to patient-level radiomic normograms to predict myocardial infarction using univariate and multivariate Cox proportional hazard models. Results The study cohort comprised of 260 patients with established CAD (age: 65±9 years; 84% men); 179 (69%) participants showed increased coronary 18F-NaF activity (CMA &amp;gt;0). Over 53 [40–59] months of follow-up 18 patients had a myocardial infarction. Using weighted correlation network analysis, from the 1103 radiomic features we derived 15 distinct eigen radiomic features representing latent morphological coronary plaque patterns. On univariate cox modelling 7 of these emerged as predictors of myocardial infarction (Figure). Following adjustments for calcified, noncalcified and low-density noncalcified plaque volumes and 18F-NaF CMA 4 radiomic features (related to texture and geometry) remained independent predictors of myocardial infarction (Figure). Conclusion(s) In patients with established CAD latent morphological features of coronary plaques are predictors of myocardial infarction above and beyond plaque volumes and 18F-NaF uptake. Comprehensive plaque analysis with radiomics may enhance risk stratification of CAD patients. Funding Acknowledgement Type of funding sources: Public grant(s) – National budget only. Main funding source(s): NIH, Wellcome Trust

Longitudinal monitoring of fetlock lesions in Thoroughbred racehorses using standing 18F-sodium fluoride positron emission tomography.

To assess the repeatability of equine 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) findings, and to evaluate the ability of PET to monitor the progression of areas of increased radiopharmaceutical uptake (IRU) in the fetlocks of Thoroughbred racehorses. 25 racehorses with clinical signs related to fetlock injuries. This study is a prospective, longitudinal clinical study. Twenty-five racehorses (54 fetlocks) underwent three 18F-NaF PET scans 6 weeks apart. The first 18F-NaF PET scan was performed at the start of a 12-week period of rest from racing (lay-up). Areas of IRU in the fetlock joints were quantified using maximal standardized uptake values (SUVmax) and were graded by 2 experienced observers. Statistical comparisons were made between scans to detect changes in IRU grade and SUVmax over time. Standing PET findings were repeatable, with 131/149 (88%) areas of IRU identified on the initial scans seen again at the 6-week follow-up scan. The palmar/plantar condyles were the sites most commonly presenting with IRU, followed by the proximal sesamoid bones. Overall, 65% of fetlocks demonstrated improvement in IRU grade during the 12-week period of rest from racing. Areas of higher IRU grade took longer to resolve than the lower graded areas. Standing PET findings in the racehorse fetlock were repeatable. The SUV-based grading system may be helpful when determining appropriate lay-up duration for Thoroughbred racehorses. PET may be used to monitor areas of the fetlock involved in catastrophic breakdown injuries in Thoroughbred racehorses.