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Objectives: The purpose of this study was to investigate whether thoracic 18F-sodium fluoride positron emission tomography (PET) could improve the identification of patients at the highest risk of ischemic stroke. Background: Aortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke. Methods: In a post hoc observational cohort study, we quantified thoracic aortic and coronary 18F-sodium fluoride activity in 461 patients with stable cardiovascular disease undergoing PET combined with computed tomography (CT). Progression of atherosclerosis was assessed by change in aortic and coronary CT calcium volume. Clinical outcomes were determined by the occurrence of ischemic stroke and myocardial infarction. We compared the prognostic utility of 18F-sodium fluoride activity for predicting stroke to clinical risk scores and CT calcium quantification using survival analysis and multivariable Cox regression. Results: After 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aortic 18F-sodium fluoride activity (n = 140; r = 0.31; P = 0.00016). In 461 patients, 23 (5%) patients experienced an ischemic stroke and 32 (7%) a myocardial infarction after 6.1 ± 2.3 years of follow-up. High thoracic aortic 18F-sodium fluoride activity was strongly associated with ischemic stroke (HR: 10.3 [3.1 to 34.8]; P = 0.00017), but not myocardial infarction (P = 0.40). Conversely, high coronary 18F-sodium fluoride activity was associated with myocardial infarction (HR: 4.8 [1.9 to 12.2]; P = 0.00095) but not ischemic stroke (P = 0.39). In a multivariable Cox regression model including imaging and clinical risk factors, thoracic aortic 18F-sodium fluoride activity was the only variable associated with ischemic stroke (HR: 8.19 (2.33 to 28.7), P = 0.0010). Conclusions: In patients with established cardiovascular disease, thoracic aortic 18F-sodium fluoride activity is associated with the progression of atherosclerosis and future ischemic stroke. Arterial 18F-sodium fluoride activity identifies localized areas of atherosclerotic disease activity that are directly linked to disease progression and downstream regional clinical atherothrombotic events. (DIAMOND - Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND], NCT02110303; Study Investigating the Effect of Drugs Used to Treat Osteoporosis on the Progression of Calcific Aortic Stenosis [SALTIRE II], NCT02132026; Novel Imaging Approaches To Identify Unstable Coronary Plaques, NCT01749254; and Role of Active Valvular Calcification and Inflammation in Patients With Aortic Stenosis, NCT01358513).

Aims Coronary artery calcification is a marker of cardiovascular risk, but its association with qualitatively and quantitatively assessed plaque subtypes is unknown. Methods and results In this post-hoc analysis, computed tomography (CT) images and 5-year clinical outcomes were assessed in SCOT-HEART trial participants. Agatston coronary artery calcium score (CACS) was measured on non-contrast CT and was stratified as zero (0 Agatston units, AU), minimal (1–9 AU), low (10–99 AU), moderate (100–399 AU), high (400–999 AU), and very high (≥1000 AU). Adverse plaques were investigated by qualitative (visual categorization of positive remodelling, low-attenuation plaque, spotty calcification, and napkin ring sign) and quantitative (calcified, non-calcified, low-attenuation, and total plaque burden; Autoplaque) assessments. Of 1769 patients, 36% had a zero, 9% minimal, 20% low, 17% moderate, 10% high, and 8% very high CACS. Amongst patients with a zero CACS, 14% had non-obstructive disease, 2% had obstructive disease, 2% had visually assessed adverse plaques, and 13% had low-attenuation plaque burden >4%. Non-calcified and low-attenuation plaque burden increased between patients with zero, minimal, and low CACS (P 1000 AU and low-attenuation plaque burden were the only predictors of myocardial infarction, independent of obstructive disease, and 10-year cardiovascular risk score. Conclusion In patients with stable chest pain, zero CACS is associated with a good but not perfect prognosis, and CACS cannot rule out obstructive coronary artery disease, non-obstructive plaque, or adverse plaque phenotypes, including low-attenuation plaque.

Objectives Cardiac MR is widely used to diagnose cardiac amyloid, but cannot differentiate AL and ATTR subtypes: an important distinction given their differing treatments and prognoses. We used PET/MR imaging to quantify myocardial uptake of 18F-fluoride in ATTR and AL amyloid patients, as well as participants with aortic stenosis and age/sex-matched controls. Methods In this prospective multicenter study, patients were recruited in Edinburgh and New York and underwent 18F-fluoride PET/MR imaging. Standardized volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardized uptake values (SUV) and tissue-to-background ratio (TBRMEAN) after correction for blood pool activity in the right atrium. Results 53 patients were scanned: 18 with cardiac amyloid (10 ATTR and 8 AL), 13 controls, and 22 with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in ATTR amyloid (1.13 ± 0.16) were higher than controls (0.84 ± 0.11, P = .0006), aortic stenosis (0.73 ± 0.12, P < .0001), and those with AL amyloid (0.96 ± 0.08, P = .01). TBRMEAN values within areas of late gadolinium enhancement provided discrimination between patients with ATTR (1.36 ± 0.23) and all other groups (e.g., AL [1.06 ± 0.07, P = .003]). A TBRMEAN threshold >1.14 in areas of LGE demonstrated 100% sensitivity (CI 72.25 to 100%) and 100% specificity (CI 67.56 to 100%) for ATTR compared to AL amyloid (AUC 1, P = .0004). Conclusion Quantitative 18F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds promise in improving the diagnosis of this condition.

Background Challenges to cardiac PET-CT include patient motion, prolonged image acquisition and a reduction of counts due to gating. We compared two analytical tools, FusionQuant and OsiriX, for quantification of gated cardiac 18F-sodium fluoride (18F-fluoride) PET-CT imaging. Methods Twenty-seven patients with aortic stenosis were included, 15 of whom underwent repeated imaging 4 weeks apart. Agreement between analytical tools and scan-rescan reproducibility was determined using the Bland-Altman method and Lin's concordance correlation coefficients (CCC). Results Image analysis was faster with FusionQuant [median time (IQR) 7:10 (6:40-8:20) minutes] compared with OsiriX [8:30 (8:00-10:10) minutes,p = .002]. Agreement of uptake measurements between programs was excellent, CCC = 0.972 (95% CI 0.949-0.995) for mean tissue-to-background ratio (TBRmean) and 0.981 (95% CI 0.965-0.997) for maximum tissue-to-background ratio (TBRmax). Mean noise decreased from 11.7% in the diastolic gate to 6.7% in motion-corrected images (p = .002); SNR increased from 25.41 to 41.13 (p = .0001). Aortic valve scan-rescan reproducibility for TBR(max)was improved with FusionQuant using motion correction compared to OsiriX (error +/- 36% vs +/- 13%,p < .001) while reproducibility for TBR(mean)was similar (+/- 10% vs +/- 8%p = .252). Conclusion 18F-fluoride PET quantification with FusionQuant and OsiriX is comparable. FusionQuant with motion correction offers advantages with respect to analysis time and reproducibility of TBR(max)values.

Supplemental Digital Content is available in the text., Background: The future risk of myocardial infarction is commonly assessed using cardiovascular risk scores, coronary artery calcium score, or coronary artery stenosis severity. We assessed whether noncalcified low-attenuation plaque burden on coronary CT angiography (CCTA) might be a better predictor of the future risk of myocardial infarction. Methods: In a post hoc analysis of a multicenter randomized controlled trial of CCTA in patients with stable chest pain, we investigated the association between the future risk of fatal or nonfatal myocardial infarction and low-attenuation plaque burden (% plaque to vessel volume), cardiovascular risk score, coronary artery calcium score or obstructive coronary artery stenoses. Results: In 1769 patients (56% male; 58±10 years) followed up for a median 4.7 (interquartile interval, 4.0–5.7) years, low-attenuation plaque burden correlated weakly with cardiovascular risk score (r=0.34; P

Background Lipoprotein(a) [Lp(a)] is associated with increased risk of myocardial infarction, although the mechanism for this observation remains uncertain. Objectives This study aims to investigate whether Lp(a) is associated with adverse plaque progression. Methods Lp(a) was measured in patients with advanced stable coronary artery disease undergoing coronary computed tomography angiography at baseline and 12 months to assess progression of total, calcific, noncalcific, and low-attenuation plaque (necrotic core) in particular. High Lp(a) was defined as Lp(a) ≥ 70 mg/dL. The relationship of Lp(a) with plaque progression was assessed using linear regression analysis, adjusting for body mass index, segment involvement score, and ASSIGN score (a Scottish cardiovascular risk score comprised of age, sex, smoking, blood pressure, total and high-density lipoprotein [HDL]–cholesterol, diabetes, rheumatoid arthritis, and deprivation index). Results A total of 191 patients (65.9 ± 8.3 years of age; 152 [80%] male) were included in the analysis, with median Lp(a) values of 100 (range: 82 to 115) mg/dL and 10 (range: 5 to 24) mg/dL in the high and low Lp(a) groups, respectively. At baseline, there was no difference in coronary artery disease severity or plaque burden. Patients with high Lp(a) showed accelerated progression of low-attenuation plaque compared with low Lp(a) patients (26.2 ± 88.4 mm3 vs −0.7 ± 50.1 mm3; P = 0.020). Multivariable linear regression analysis confirmed the relation between Lp(a) and low-attenuation plaque volume progression (β = 10.5% increase for each 50 mg/dL Lp(a), 95% CI: 0.7%-20.3%). There was no difference in total, calcific, and noncalcific plaque volume progression. Conclusions Among patients with advanced stable coronary artery disease, Lp(a) is associated with accelerated progression of coronary low-attenuation plaque (necrotic core). This may explain the association between Lp(a) and the high residual risk of myocardial infarction, providing support for Lp(a) as a treatment target in atherosclerosis., Central Illustration

Supplemental Digital Content is available in the text., Background: Major uncertainties remain regarding disease activity within the retained native aortic valve, and regarding bioprosthetic valve durability, after transcatheter aortic valve implantation (TAVI). We aimed to assess native aortic valve disease activity and bioprosthetic valve durability in patients with TAVI in comparison with subjects with bioprosthetic surgical aortic valve replacement (SAVR). Methods: In a multicenter cross-sectional observational cohort study, patients with TAVI or bioprosthetic SAVR underwent baseline echocardiography, computed tomography angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography. Participants (n=47) were imaged once with 18F-NaF positron emission tomography/computed tomography either at 1 month (n=9, 19%), 2 years (n=22, 47%), or 5 years (16, 34%) after valve implantation. Patients subsequently underwent serial echocardiography to assess for changes in valve hemodynamic performance (change in peak aortic velocity) and evidence of structural valve dysfunction. Comparisons were made with matched patients with bioprosthetic SAVR (n=51) who had undergone the same imaging protocol. Results: In patients with TAVI, native aortic valves demonstrated 18F-NaF uptake around the outside of the bioprostheses that showed a modest correlation with the time from TAVI (r=0.36, P=0.023). 18F-NaF uptake in the bioprosthetic leaflets was comparable between the SAVR and TAVI groups (target-to-background ratio, 1.3 [1.2–1.7] versus 1.3 [1.2–1.5], respectively; P=0.27). The frequencies of imaging evidence of bioprosthetic valve degeneration at baseline were similar on echocardiography (6% versus 8%, respectively; P=0.78), computed tomography (15% versus 14%, respectively; P=0.87), and positron emission tomography (15% versus 29%, respectively; P=0.09). Baseline 18F-NaF uptake was associated with a subsequent change in peak aortic velocity for both TAVI (r=0.7, P

Background Arterial 18F-sodium fluoride (18F-NaF) activity on positron emission tomography (PET) is a marker of active microcalcification and atherosclerosis. Coronary 18F-NaF activity (CMA) predicts coronary artery disease progression and subsequent myocardial infarction. Objective To investigate whether aortic 18F-NaF activity (AMA) predicts thoracic aortic atherosclerotic disease progression and subsequent ischaemic stroke or myocardial infarction in patients with established cardiovascular disease. Methods In a post-hoc observational cohort study, we evaluated AMA and CMA in patients with stable coronary artery disease (n=239) or aortic stenosis (n=158) who had underwent thoracic 18F-NaF PET and computed tomography (CT). We assessed the associations between AMA or CMA and progression of calcified atherosclerotic plaque in both thoracic aortic and coronary territories on follow up CT, as well as subsequent ischaemic stroke or myocardial infarction. Results In 141 and 231 patients with repeat aortic and coronary CT imaging respectively at 12.7±2.7 months, AMA correlated with log progression of thoracic aortic calcium scores (r=0.21, p=0.011), volume (r=0.29, p0.80) calcium score progression. In 397 patients, 16 had an ischaemic stroke and 25 had a myocardial infarction after 4.7±1.6 years. After adjusting for clinical risk factors, CMA and calcium scoring, AMA was associated with stroke (hazard ratio, 1.71 [95% confidence interval 1.00–2.90], p=0.048]). AMA was superior to clinical risk and calcium scores in identifying patients with stroke (c-statistic 0.76 versus 0.58 versus 0.63 respectively, p Conclusions In patients with established cardiovascular disease, AMA is associated with progression of aortic atherosclerosis and future ischaemic stroke. Arterial 18F-NaF identifies localised areas of atherosclerotic disease activity that relate to regional atherothrombotic events. Funding Acknowledgement Type of funding sources: Other. Main funding source(s): British Heart Foundation AMA, disease progression and outcomesVariables associated with stroke

Aortic atherosclerosis represents an important contributor to ischemic stroke risk. Identifying patients with high-risk aortic atheroma could improve preventative treatment strategies for future ischemic stroke.The purpose of this study was to investigate whether thoracicIn a post hoc observational cohort study, we quantified thoracic aortic and coronaryAfter 12.7 ± 2.7 months, progression of thoracic aortic calcium volume correlated with baseline thoracic aorticIn patients with established cardiovascular disease, thoracic aortic

Background 18F-Fluoride uptake denotes calcification activity in aortic stenosis and atherosclerosis. While PET/MR has several advantages over PET/CT, attenuation correction of PET/MR data is challenging, limiting cardiovascular application. We compared PET/MR and PET/CT assessments of 18F-fluoride uptake in the aortic valve and coronary arteries. Methods and results 18 patients with aortic stenosis or recent myocardial infarction underwent 18F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as tissue-to-background ratios (TBRs). Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58 ± 0.34, P = 0.66; 95% limits of agreement − 27% to + 25%) but performed less well with Dixon AC (1.38 ± 0.44, P = 0.06; bias (−)14%; 95% limits of agreement − 25% to + 53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT; however, stents caused artifact on PET/MR making assessment of 18F-fluoride uptake challenging. Conclusion Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artifacts currently limiting clinical application.

Introduction Pericoronary adipose tissue (PCAT) attenuation has emerged as a surrogate marker of pericoronary inflammation. To date, no studies have compared the impact of pericoronary adipose tissue(PCAT) attenuation and quantitative plaque burden on cardiac outcomes. We aimed to establish the relative merits of these approaches to risk prediction and hypothesised that the combination of PCAT attenuation and quantitative plaque burden measures could provide additive and improved prediction of myocardial infarction in patients with stable chest pain. Methods In a post-hoc analysis of a randomized controlled trial, we investigated the association between the future risk of fatal or non-fatal myocardial infarction and PCAT attenuation measured from CT coronary angiography using multivariable Cox regression models including plaque burden, obstructive coronary disease and cardiac risk score (incorporating age, sex, diabetes, smoking, hypertension, hyperlipidaemia and family history of cardiovascular disease). Results In 1697 evaluable participants (mean age 58±10 years), there were 37 myocardial infarctions after a median follow-up of 4.7 [interquartile interval, 4.0-5.7] years. Median low-attenuation plaque burden was 4.20[0-6.86] % and mean PCAT -76±8 Hounsfield units (HU). PCAT-RCA attenuation was higher in patients who suffered a myocardial infarction (-72.5±8.3 HU versus -76.5± 7.8 HU, p=0.0063), but there was no difference in PCAT-LAD (-76.3±8.6 HU vs -77.0±7.8 HU, p=0.54) or PCAT-LCx(-71.6±7.3 HU vs -73.3±7.7 HU, p=0.33). Patients sustaining a myocardial infarction also had higher total, non-calcified, low-attenuation and calcified plaque burden, higher Agatston calcium score, higher cardiovascular risk score and increased presence of obstructive disease on CCTA (table 1). On univariable analysis, PCAT-RCA attenuation was a predictor of myocardial infarction (HR 1.55, 95% CI 1.08 to 2.22, p=0.017), but PCAT-LAD or PCAT-LCx were not. Univariable analysis also identified the burden of non-calcified, low-attenuation and calcified plaque as well as Agatston coronary calcium score, presence of obstructive coronary artery disease and cardiovascular risk score were predictors of myocardial infarction (table 2). Male sex, age and body-mass index were not predictors of future myocardial infarction (p=0.06, p=0.86 and 0.26 respectively). In multivariable analysis, only the low-attenuation plaque burden (HR 1.80, 95% CI 1.16 to 2.81, p=0.011, per doubling) and PCAT-RCA (HR 1.47 95%1.02 to 2.13, p=0.040, per standard deviation increment) remained predictors of myocardial infarction (table 2). Based on the Youden’s index of the ROC curves, the optimal cut-off of the right coronary artery PCAT attenuation was –70.5 HU for the primary endpoint of fatal or non-fatal myocardial infarction. Patients with PCAT-RCA above ≥–70.5 HU were nearly 2.5 times more likely to suffer a myocardial infarction (HR 2.45, 95% CI 1.23 to 4.80; p=0.001). Patients with low-attenuation plaque burden (greater than 4%) were nearly 5 times more likely to suffer a myocardial infarction (HR 4.87, 95% CI 2.03 to 11.78, p 4% and PCAT-RCA ≥-70.5 HU were at the greatest risk of myocardial infarction (HR 11.7, 95% CI 3.3 to 40.9, p 4% and PCAT-RCA Conclusion CT coronary angiography defined PCAT attenuation and low-attenuation plaque have marked and additive predictive value for the risk of fatal or non-fatal myocardial infarction. Conflict of Interest Nil

Background: Valvular calcification is central to the pathogenesis and progression of aortic stenosis, with preclinical and observational studies suggesting that bone turnover and osteoblastic differentiation of valvular interstitial cells are important contributory mechanisms. We aimed to establish whether inhibition of these pathways with denosumab or alendronic acid could reduce disease progression in aortic stenosis. Methods: In a single-center, parallel group, double-blind randomized controlled trial, patients >50 years of age with calcific aortic stenosis (peak aortic jet velocity >2.5 m/s) were randomized 2:1:2:1 to denosumab (60 mg every 6 months), placebo injection, alendronic acid (70 mg once weekly), or placebo capsule. Participants underwent serial assessments with Doppler echocardiography, computed tomography aortic valve calcium scoring, and 18 F-sodium fluoride positron emission tomography and computed tomography. The primary end point was the calculated 24-month change in aortic valve calcium score. Results: A total of 150 patients (mean age, 72±8 years; 21% women) with calcific aortic stenosis (peak aortic jet velocity, 3.36 m/s [2.93–3.82 m/s]; aortic valve calcium score, 1152 AU [655–2065 AU]) were randomized and received the allocated trial intervention: denosumab (n=49), alendronic acid (n=51), and placebo (injection n=25, capsule n=25; pooled for analysis). Serum C-terminal telopeptide, a measure of bone turnover, halved from baseline to 6 months with denosumab (0.23 [0.18–0.33 µg/L] to 0.11 µg/L [0.08–0.17 µg/L]) and alendronic acid (0.20 [0.14–0.28 µg/L] to 0.09 µg/L [0.08–0.13 µg/L]) but was unchanged with placebo (0.23 [0.17–0.30 µg/L] to 0.26 µg/L [0.16–0.31 µg/L]). There were no differences in 24-month change in aortic valve calcium score between denosumab and placebo (343 [198–804 AU] versus 354 AU [76–675 AU]; P=0.41) or alendronic acid and placebo (326 [138–813 AU] versus 354 AU [76–675 AU]; P =0.49). Similarly, there were no differences in change in peak aortic jet velocity or 18 F-sodium fluoride aortic valve uptake. Conclusions: Neither denosumab nor alendronic acid affected progression of aortic valve calcification in patients with calcific aortic stenosis. Alternative pathways and mechanisms need to be explored to identify disease-modifying therapies for the growing population of patients with this potentially fatal condition. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02132026.

OBJECTIVES: This study was designed to investigate whether coronary computed tomography angiography assessments of coronary plaque might explain differences in the prognosis of men and women presenting with chest pain. BACKGROUND: Important sex differences exist in coronary artery disease. Women presenting with chest pain have different risk factors, symptoms, prevalence of coronary artery disease and prognosis compared to men. METHODS: Within a multicenter randomized controlled trial, we explored sex differences in stenosis, adverse plaque characteristics (positive remodeling, low-attenuation plaque, spotty calcification, or napkin ring sign) and quantitative assessment of total, calcified, noncalcified and low-attenuation plaque burden. RESULTS: Of the 1,769 participants who underwent coronary computed tomography angiography, 772 (43%) were female. Women were more likely to have normal coronary arteries and less likely to have adverse plaque characteristics (p < 0.001 for all). They had lower total, calcified, noncalcified, and low-attenuation plaque burdens (p < 0.001 for all) and were less likely to have a low-attenuation plaque burden >4% (41% vs. 59%; p < 0.001). Over a median follow-up of 4.7 years, myocardial infarction (MI) occurred in 11 women (1.4%) and 30 men (3%). In those who had MI, women had similar total, noncalcified, and low-attenuation plaque burdens as men, but men had higher calcified plaque burden. Low-attenuation plaque burden predicted MI (hazard ratio: 1.60; 95% confidence interval: 1.10 to 2.34; p = 0.015), independent of calcium score, obstructive disease, cardiovascular risk score, and sex. CONCLUSIONS: Women presenting with stable chest pain have less atherosclerotic plaque of all subtypes compared to men and a lower risk of subsequent MI. However, quantitative low-attenuation plaque is as strong a predictor of subsequent MI in women as in men. (Scottish Computed Tomography of the HEART Trial [SCOT-HEART]; NCT01149590).

Background Standard methods for quantifying positron emission tomography (PET) uptake in the aorta are time consuming and may not reflect overall vessel activity. We describe aortic microcalcification activity (AMA), a novel method for quantifying 18F-sodium fluoride (18F-NaF) uptake in the thoracic aorta. Methods Twenty patients underwent two hybrid 18F-NaF PET and computed tomography (CT) scans of the thoracic aorta less than three weeks apart. AMA, as well as maximum (TBRmax) and mean (TBRmean) tissue to background ratios, were calculated by two trained operators. Intra-observer repeatability, inter-observer repeatability and scan-rescan reproducibility were assessed. Each 18F-NaF quantification method was compared to validated cardiovascular risk scores. Results Aortic microcalcification activity demonstrated excellent intra-observer (intraclass correlation coefficient 0.98) and inter-observer (intraclass correlation coefficient 0.97) repeatability with very good scan-rescan reproducibility (intraclass correlation coefficient 0.86) which were similar to previously described TBRmean and TBRmax methods. AMA analysis was much quicker to perform than standard TBR assessment (3.4min versus 15.1min, P Conclusions AMA is a simple, rapid and reproducible method of quantifying global 18F-NaF uptake across the ascending aorta and aortic arch that correlates with cardiovascular risk scores.

Background: Atherosclerotic plaque quantification from coronary computed tomography angiography (CCTA) enables accurate assessment of coronary artery disease burden and prognosis. We sought to develop and externally validate a deep learning (DL) system for CCTA-derived measures of plaque volume and stenosis severity. Methods: This was an international multicenter study of patients undergoing CCTA at 11 sites. A novel DL convolutional neural network was trained to segment coronary plaque in 921 patients (5,045 lesions). The DL network was then applied to an independent test set, which included an external validation cohort of 175 patients (1,081 lesions) as well 50 patients (84 lesions) assessed by intravascular ultrasound (IVUS) within one month of CCTA. Thereafter, we evaluated the prognostic value of DL-based plaque measurements for fatal or nonfatal myocardial infarction (MI) in 1,611 patients from the prospective SCOT-HEART trial. Findings: In the overall test set, there was excellent agreement between DL and expert reader measurements of total plaque volume (intraclass correlation coefficient [ICC] 0·964) and percent diameter stenosis (ICC 0·879; both p

ObjectivesNon-contrast CT aortic valve calcium scoring ignores the contribution of valvular fibrosis in aortic stenosis. We assessed aortic valve calcific and non-calcific disease using contrast-enhanced CT.MethodsThis was a post hoc analysis of 164 patients (median age 71 (IQR 66–77) years, 78% male) with aortic stenosis (41 mild, 89 moderate, 34 severe; 7% bicuspid) who underwent echocardiography and contrast-enhanced CT as part of imaging studies. Calcific and non-calcific (fibrosis) valve tissue volumes were quantified and indexed to annulus area, using Hounsfield unit thresholds calibrated against blood pool radiodensity. The fibrocalcific ratio assessed the relative contributions of valve fibrosis and calcification. The fibrocalcific volume (sum of indexed non-calcific and calcific volumes) was compared with aortic valve peak velocity and, in a subgroup, histology and valve weight.ResultsContrast-enhanced CT calcium volumes correlated with CT calcium score (r=0.80, p3/cm2). Fibrocalcific volume correlated with ex vivo valve weight (r=0.72, pConclusionsContrast-enhanced CT assessment of aortic valve calcific and non-calcific volumes correlates with aortic stenosis severity and may be preferable to non-contrast CT when fibrosis is a significant contributor to valve obstruction.

Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): This work was supported by the British Heart Foundation, London, United Kingdom Background Early detection of transcatheter aortic valve implantation (TAVI) degeneration is challenging and only feasible when advanced haemodynamic valve dysfunction is apparent. Purpose We tested whether 18F-sodium fluoride (18F-NaF) positron emission tomography and computed tomography (PET/CT) could detect structural TAVI degeneration and haemodynamic valve dysfunction. Methods After TAVI implantation, patients underwent baseline echocardiography, CT angiography and 18F-NaF PET/CT (Figure). We assessed for morphological changes, stenosis or regurgitation on Doppler echocardiography, CT (hypoattenuated leaflet thickening [HALT] or spotty calcification) and PET (18F-NaF uptake; maximum target-to-background ratio, TBRmax). We categorised structural valve degeneration (SVD) according to the standardised definition for surgical and transcatheter bioprosthetic valves, as proposed in a recent consensus statement. Results We recruited 47 patients (81 ± 6 years old, 79% male) 1 month (n = 9), 2 years (n = 22) or 5 years (n = 16) after TAVI: 25 (53%) had received a balloon expanded bioprosthesis and 22 (47%) a self-expanding valve. There was moderate valve dysfunction on Doppler echocardiography in 3 (6%) patients, HALT on CT in 6 (13%) patients, spotty calcification in one patient and 18F-NaF uptake in 7 patients (15%) (TBRmax range: 1.59-5.88); all enrolled 5 years post-TAVI. All patients with increased 18F-NaF uptake (TBRmax ≥1.59) demonstrated either SVD without haemodynamic valve dysfunction (stage 1, n = 4) or structural valve dysfunction with moderate valve dysfunction and mean transprosthetic pressure gradients >20 mmHg (stage 2, n = 3). In patients without increased 18F-NaF uptake there was no evidence of structural valve degeneration (n = 40). Within the increased 18F-NaF uptake (n = 7) group, patients with stage 2 SVD (n = 3) demonstrated higher uptake compared to patients with stage 1 SVD (TBRmax 4.3 [3.02-5.88] versus 1.8 [1.59-2.28]). Patients with stage 2 SVD (n = 3) had over 3 times higher TBRmax than those without SVD (n = 40) (4.30 [3.02, 5.88] versus 1.31 [1.21, 1.46]; p Conclusion 18F-NaF PET/CT detects patients with SVD and potentially identifies those at risk of valve failure. Abstract Figure.

Background Positron emission tomography (PET) using

Background Positron emission tomography (PET) using 18 F-sodium fluoride ( 18 F-fluoride) to detect microcalcification may provide insight into disease activity in coronary atherosclerosis. This study aimed to investigate the relationship between 18 F-fluoride uptake and progression of coronary calcification in patients with clinically stable coronary artery disease. Methods Patients with established multivessel coronary atherosclerosis underwent 18 F-fluoride PET-computed tomography angiography and computed tomography calcium scoring, with repeat computed tomography angiography and calcium scoring at one year. Coronary PET uptake was analyzed qualitatively and semiquantitatively in diseased vessels by measuring maximum tissue-to-background ratio. Coronary calcification was quantified by measuring calcium score, mass, and volume. Results In a total of 183 participants (median age 66 years, 80% male), 116 (63%) patients had increased 18 F-fluoride uptake in at least one vessel. Individuals with increased 18 F-fluoride uptake demonstrated more rapid progression of calcification compared with those without uptake (change in calcium score, 97 [39–166] versus 35 [7–93] AU; P 18 F-fluoride uptake (from 95 [30–209] to 148 [61–289] AU; P 18 F-fluoride uptake (from 46 [16–113] to 49 [20–115] AU; P =0.329). Baseline coronary 18 F-fluoride maximum tissue-to-background ratio correlated with 1-year change in calcium score, calcium volume, and calcium mass (Spearman ρ=0.37, 0.38, and 0.46, respectively; P 18 F-fluoride activity was an independent predictor of calcium score at 12 months ( P P =0.50). Conclusions Coronary 18 F-fluoride uptake identifies both patients and individual coronary segments with more rapid progression of coronary calcification, providing important insights into disease activity within the coronary circulation. At the individual patient level, total calcium score remains an important marker of disease burden and progression. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02110303.

Early microcalcification is a feature of coronary plaques with an increased propensity to rupture and to cause acute coronary syndromes. In this ex vivo imaging study of coronary artery specimens, the non-invasive imaging radiotracer, 18F-fluoride, was highly selective for hydroxyapatite deposition in atherosclerotic coronary plaque. Specifically, coronary 18F-fluoride uptake had a high signal to noise ratio compared with surrounding myocardium that makes it feasible to identify coronary mineralisation activity. Areas of 18F-fluoride uptake are associated with osteopontin, an inflammation-associated glycophosphoprotein that mediates tissue mineralisation, and Runt-related transcription factor 2, a nuclear protein involved in osteoblastic differentiation. These results suggest that 18F-fluoride is a non-invasive imaging biomarker of active coronary atherosclerotic mineralisation.

Introduction Cardiac MR is widely used to diagnose cardiac amyloid but cannot differentiate AL and ATTR subtypes: an important distinction given their differing treatments and prognoses. We used PET/MR imaging to quantify myocardial uptake of 18F-fluoride in ATTR and AL amyloid patients as well as participants with aortic stenosis and age/sex matched controls (both negative controls). Methods In this prospective multi-centre study, patients were recruited in Edinburgh and New York and underwent 18F-fluoride PET/MR imaging. Standardised volumes of interest were drawn in the septum and areas of late gadolinium enhancement to derive myocardial standardised uptake values (SUV) and tissue to background ratio (TBRMEAN) after correction for blood pool activity in the right atrium. Results 53 patients were scanned. 18 with cardiac amyloid (10 ATTR and 8 AL), 13 controls and 22 with aortic stenosis. No differences in myocardial TBR values were observed between participants scanned in Edinburgh and New York. Mean myocardial TBRMEAN values in ATTR amyloid (1.13±0.16) were significantly higher than controls (0.84±0.11, p=0.0006), aortic stenosis (0.73±0.12, p 1.14 in areas of LGE demonstrated 100% sensitivity (C.I. 72.25 – 100%) and 100% specificity (C.I. 67.56 – 100%) for ATTR compared to AL amyloid (AUC 1, p=0.0004). Conclusion Quantitative 18F-fluoride PET/MR imaging can distinguish ATTR amyloid from other similar phenotypes and holds major promise in improving the diagnosis of this condition and helping to tailor appropriate treatments to those most likely to benefit.

ObjectiveCT quantification of aortic valve calcification (CT-AVC) is useful in the assessment of aortic stenosis severity. Our objective was to assess its ability to track aortic stenosis progression compared with echocardiography.MethodsSubjects were recruited in two cohorts: (1) a reproducibility cohort where patients underwent repeat CT-AVC or echocardiography within 4 weeks and (2) a disease progression cohort where patients underwent annual CT-AVC and/or echocardiography. Cohen’s d-statistic (d) was computed from the ratio of annualised progression and measurement repeatability and used to estimate group sizes required to detect annualised changes in CT-AVC and echocardiography.ResultsA total of 33 (age 71±8) and 81 participants (age 72±8) were recruited to the reproducibility and progression cohorts, respectively. Ten CT scans (16%) were excluded from the progression cohort due to non-diagnostic image quality. Scan-rescan reproducibility was excellent for CT-AVC (limits of agreement −12% to 10 %, intraclass correlation (ICC) 0.99), peak velocity (−7% to +17%; ICC 0.92) mean gradient (−25% to 27%, ICC 0.96) and dimensionless index (−11% to +15%; ICC 0.98). Repeat measurements of aortic valve area (AVA) were less reliable (−44% to +28%, ICC 0.85).CT-AVC progressed by 152 (65–375) AU/year. For echocardiography, the median annual change in peak velocity was 0.1 (0.0–0.3) m/s/year, mean gradient 2 (0–4) mm Hg/year and AVA −0.1 (−0.2–0.0) cm2/year. Cohen’s d-statistic was more than double for CT-AVC (d=3.12) than each echocardiographic measure (peak velocity d=0.71 ; mean gradient d=0.66; AVA d=0.59, dimensionless index d=1.41).ConclusionCT-AVC is reproducible and demonstrates larger increases over time normalised to measurement repeatability compared with echocardiographic measures.

BACKGROUND: Coronary PET shows promise in the detection of high-risk atherosclerosis, but there remains a need to optimize imaging and reconstruction techniques. We investigated the impact of reconstruction parameters and cardiac motion-correction in 18F Sodium Fluoride (18F-NaF) PET.METHODS: Twenty-two patients underwent 18F-NaF PET within 22 days of an acute coronary syndrome. Optimal reconstruction parameters were determined in a subgroup of six patients. Motion-correction was performed on ECG-gated data of all patients with optimal reconstruction. Tracer uptake was quantified in culprit and reference lesions by computing signal-to-noise ratio (SNR) in diastolic, summed, and motion-corrected images.RESULTS: Reconstruction using 24 subsets, 4 iterations, point-spread-function modelling, time of flight, and 5-mm post-filtering provided the highest median SNR (31.5) compared to 4 iterations 0-mm (22.5), 8 iterations 0-mm (21.1), and 8 iterations 5-mm (25.6; all P CONCLUSIONS: The number of iterations and extent of post-filtering has marked effects on coronary 18F-NaF PET quantification. Cardiac motion-correction improves discrimination between culprit and reference lesions.

Calcification is one of the key processes driving progression of aortic stenosis (AS), alongside inflammation and fibrosis ([1][1]). Women require less aortic valve calcification on multidetector computed tomography (CT-AVC) to develop severe AS than men, even after accounting for body size. In line

Objectives This study aimed to assess the association between increased lesion peri-coronary adipose tissue (PCAT) density and coronary 18F-sodium fluoride (18F-NaF) uptake on positron emission tomography (PET) in stable patients with high-risk coronary plaques (HRPs) shown on coronary computed tomography angiography (CTA). Background Coronary 18F-NaF uptake reflects the rate of calcification of coronary atherosclerotic plaque. Increased PCAT density is associated with vascular inflammation. Currently, the relationship between increased PCAT density and 18F-NaF uptake in stable patients with HRPs on coronary CTA has not been characterized. Methods Patients who underwent coronary CTA were screened for HRP, which was defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP) (100 mm3). Patients with HRPs were recruited to undergo 18F-NaF PET/CT. In lesions with stenosis ≥25%, quantitative plaque analysis, mean PCAT density, maximal coronary motion−corrected 18F-NaF standard uptake values (SUVmax), and target-to-background ratios (TBR) were measured. Results Forty-one patients (age 65 ± 6 years; 68% men) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronary 18F-NaF activity. Lesions with 18F-NaF uptake had higher surrounding PCAT density than those without 18F-NaF uptake (−73 HU; interquartile range −79 to −68 HU vs. −86 HU; interquartile range −94 to −80 HU; p < 0.001). 18F-NaF TBR and SUVmax were correlated with PCAT density (r = 0.63 and r = 0.68, respectively; all p < 0.001). On adjusted multiple regression analysis, increased lesion PCAT density and LAP volume were associated with 18F-NaF TBR (β = 0.25; 95% confidence interval: 0.17 to 0.34; p < 0.001 for PCAT, and β = 0.07; 95% confidence interval: 0.03 to 0.11; p = 0.002 for LAP). Conclusions In patients with HRP features on coronary CTA, increased density of PCAT was associated with focal 18F-NaF PET uptake. Simultaneous assessment of these imaging biomarkers by 18F-NaF PET and CTA might refine cardiovascular risk prediction in stable patients with HRP features.

Background Combined positron emission tomography and computed tomography (PET-CT) using 18F-sodium fluoride (18F-NaF) to detect microcalcification provides the opportunity to gain important insights into disease activity in coronary atherosclerosis. However, the relationship between 18F-NaF uptake and progression of coronary calcification has not been determined. Purpose To determine the relationship between 18F-NaF uptake and progression of coronary calcification in patients with clinically stable coronary artery disease (CAD). Methods Patients with established, multivessel CAD underwent 18F-NaF PET-CT and CT coronary calcium scoring at baseline, with repeat CT calcium scoring at one year. Coronary arterial PET uptake was analysed qualitatively and semi-quantitatively in diseased vessels by measuring maximum tissue-to-background ratio (TBRmax) – defined as the maximum standardised uptake value in a plaque divided by mean blood pool activity measured in the right atrium. Coronary calcification was quantified by measuring calcium mass, volume, average calcium density and total Agatston score (AU). Results In total, 185 patients underwent baseline and repeat imaging (median age 66 years, 80% men), and 118 (64%) had increased 18F-NaF uptake in at least one vessel. Median total calcium score, volume, mass and average density were higher in patients with compared to those without increased 18F-NaF uptake (Table 1). At one year, patients with evidence of increased 18F-NaF uptake demonstrated more rapid progression of coronary calcification (97 [39–166] AU) versus those without uptake (35 [7–93] AU; p Coronary calcification at baseline in PET-negative and PET-positive patients All patients (n=185) 18F-NaF Positive (n=118) 18F-NaF Negative (n=67) P value Agatston Score (AU) 381 [107–892] 541 [245–1130] 136 [55–361] p Conclusions Coronary 18F-NaF uptake identifies both patients and individual coronary segments with greater disease and more rapid progression of coronary calcification over one year. Acknowledgement/Funding AstraZeneca (unrestricted educational grant). British Heart Foundation (CH/09/002, RE/13/3/30183, FS/17/79/33226) Wellcome Trust (WT103782AIA).

Background 18F-Fluoride uptake denotes calcification activity in aortic stenosis and atherosclerosis. While PET/MR has several advantages over PET/CT, attenuation correction of PET/MR data is challenging, limiting cardiovascular application. We compared PET/MR and PET/CT assessments of 18F-fluoride uptake in the aortic valve and coronary arteries. Methods and results 18 patients with aortic stenosis or recent myocardial infarction underwent 18F-fluoride PET/CT followed immediately by PET/MR. Valve and coronary 18F-fluoride uptake were evaluated independently. Both standard (Dixon) and novel radial GRE) MR attenuation correction (AC) maps were validated against PET/CT with results expressed as tissue-to-background ratios (TBRs). Visually, aortic valve 18F-fluoride uptake was similar on PET/CT and PET/MR. TBRMAX values were comparable with radial GRE AC (PET/CT 1.55±0.33 vs. PET/MR 1.58 ± 0.34, P = 0.66; 95% limits of agreement − 27% to + 25%) but performed less well with Dixon AC (1.38 ± 0.44, P = 0.06; bias (−)14%; 95% limits of agreement − 25% to + 53%). In native coronaries, 18F-fluoride uptake was similar on PET/MR to PET/CT regardless of AC approach. PET/MR identified 28/29 plaques identified on PET/CT; however, stents caused artifact on PET/MR making assessment of 18F-fluoride uptake challenging. Conclusion Cardiovascular PET/MR demonstrates good visual and quantitative agreement with PET/CT. However, PET/MR is hampered by stent-related artifacts currently limiting clinical application. Electronic supplementary material The online version of this article (10.1007/s12350-019-01962-y) contains supplementary material, which is available to authorized users.

CoronaryIn a prospective observational study, patients with multi-vessel coronary artery disease underwent serialThirty patients (90% male, 20 patients with stable coronary artery disease, and 10 with recent type 1 myocardial infarction) underwent paired serial positron emission tomography-coronary computed tomography angiography imaging within an interval of 12±5 days. A mean of 3.7±1.8CoronaryURL: http://www.clinicaltrials.gov. Unique identifiers: NCT02110303 and NCT02278211.

Background: Coronary 18 F-fluoride positron emission tomography identifies ruptured and high-risk atherosclerotic plaque. The optimal method to identify, to quantify, and to categorize increased coronary 18 F-fluoride uptake and determine its reproducibility has yet to be established. This study aimed to optimize the identification, quantification, categorization, and scan-rescan reproducibility of increased 18 F-fluoride activity in coronary atherosclerotic plaque. Methods: In a prospective observational study, patients with multi-vessel coronary artery disease underwent serial 18 F-fluoride positron emission tomography. Coronary 18 F-fluoride activity was visually assessed, quantified, and categorized with reference to maximal tissue to background ratios. Levels of agreement for both visual and quantitative methods were determined between scans and observers. Results: Thirty patients (90% male, 20 patients with stable coronary artery disease, and 10 with recent type 1 myocardial infarction) underwent paired serial positron emission tomography-coronary computed tomography angiography imaging within an interval of 12±5 days. A mean of 3.7±1.8 18 F-fluoride positive plaques per patient was identified after recent acute coronary syndrome, compared with 2.4±2.3 positive plaques per patient in stable coronary artery disease. The bias in agreement in maximum tissue to background ratio measurements in visually positive plaques was low between observers (mean difference, −0.01; 95% limits of agreement, −0.32 to 0.30) or between scans (mean difference, 0.06; 95% limits of agreement, −0.49 to 0.61). Good agreement in the categorization of focal 18 F-fluoride uptake was achieved using visual assessment alone (κ=0.66) and further improved at higher maximum tissue to background ratio values. Conclusions: Coronary 18 F-fluoride activity is a precise and reproducible metric in the coronary vasculature. The analytical performance of 18 F-fluoride is sufficient to assess the prognostic utility of this radiotracer as a noninvasive imaging biomarker of plaque vulnerability. Clinical Trial Registration: URL: http://www.clinicaltrials.gov . Unique identifiers: NCT02110303 and NCT02278211.

Introduction High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. The aim of this study is to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque using coronary 18F-fluoride positron emission tomography-computed tomography. Methods In a randomised double-blind placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography-computed tomography and measurement of high-sensitivity cardiac troponin I and were randomised (1:1) to ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. Results In total, 202 patients were randomized and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (n=120/191) there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor versus placebo, 1.11, [95% confidence interval 0.90 to 1.36], p=0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means, 0.86, 95% confidence interval 0.63 to 1.17, p=0.33). Conclusion Dual antiplatelet therapy with ticagrelor does not reduce plasma troponin concentrations in patients with coronary 18F-fluoride uptake. This suggests that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting.

Introduction Combined positron emission tomography and computed tomography (PET-CT) using the radiotracer 18F-sodium fluoride (18F-NaF) to detect microcalcification provides imaging of both coronary artery anatomy and disease activity simultaneously. While recent studies have suggested that 18F-NaF activity may help identify high-risk coronary atherosclerosis, the role of 18F-NaF uptake in predicting progression of coronary atherosclerosis is unknown. In this study, we aimed to investigate the relationship between baseline coronary arterial 18F-NaF activity and the subsequent progression of coronary arterial calcification in patients with clinically stable coronary artery disease. Methods Patients with clinically stable, multivessel coronary artery disease underwent combined 18F-NaF PET-CT and CT coronary calcium scoring at baseline with repeat CT coronary calcium scoring at one year. Coronary arterial PET uptake was analysed qualitatively and semi-quantitatively in diseased vessels by measuring maximum tissue-to-background ratio (TBRmax) – defined as the maximum standardised uptake value in a plaque divided by the mean blood pool activity measured in the right atrium. Coronary calcification was quantified by measuring calcium mass (mg), volume (mm3), average calcium density (mg/mm3) and total Agatston score (AU). Results One hundred and eighty-three patients who underwent baseline and repeat imaging at one year were included in the study (81% male, median age 66). Of these participants, 116 (63%) had evidence of increased 18F-NaF activity in at least one vessel. Patients with increased 18F-NaF uptake had a higher total calcium score (524[242–1091] AU), volume (491[247–984], mm3) mass (99[46–212] mg) and average calcium density (0.20[0.18–0.23] mg/mm3) at baseline compared to patients without increased uptake (136[55–361] AU, 131[54–343] mm3, 24[11–69] mg, 0.18[0.16–0.20] mg/mm3; P Conclusion Coronary PET-CT using 18F-NaF identifies patients with a higher calcification burden and predicts progression of coronary arterial calcification at one year. Conflict of Interest none

Objectives The goal of this study was to determine whether ticagrelor reduces high-sensitivity troponin I concentrations in patients with established coronary artery disease and high-risk coronary plaque. Background High-risk coronary atherosclerotic plaque is associated with higher plasma troponin concentrations suggesting ongoing myocardial injury that may be a target for dual antiplatelet therapy. Methods In a randomized, double-blind, placebo-controlled trial, patients with multivessel coronary artery disease underwent coronary 18F-fluoride positron emission tomography/coronary computed tomography scanning and measurement of high-sensitivity cardiac troponin I. Patients were randomized (1:1) to receive ticagrelor 90 mg twice daily or matched placebo. The primary endpoint was troponin I concentration at 30 days in patients with increased coronary 18F-fluoride uptake. Results In total, 202 patients were randomized to treatment, and 191 met the pre-specified criteria for inclusion in the primary analysis. In patients with increased coronary 18F-fluoride uptake (120 of 191), there was no evidence that ticagrelor had an effect on plasma troponin concentrations at 30 days (ratio of geometric means for ticagrelor vs. placebo: 1.11; 95% confidence interval: 0.90 to 1.36; p = 0.32). Over 1 year, ticagrelor had no effect on troponin concentrations in patients with increased coronary 18F-fluoride uptake (ratio of geometric means: 0.86; 95% confidence interval: 0.63 to 1.17; p = 0.33). Conclusions Dual antiplatelet therapy with ticagrelor did not reduce plasma troponin concentrations in patients with high-risk coronary plaque, suggesting that subclinical plaque thrombosis does not contribute to ongoing myocardial injury in this setting. (Dual Antiplatelet Therapy to Reduce Myocardial Injury [DIAMOND]; NCT02110303), Central Illustration

BACKGROUND: Mitral annular calcification (MAC) is associated with cardiovascular events and mitral valve dysfunction. However, the underlying pathophysiology remains incompletely understood. In this prospective longitudinal study, we used a multi-modality approach including positron emission tomography (PET), computed tomography (CT) and echocardiography to investigate the pathophysiology of MAC and assess factors associated with disease activity and progression. METHODS: A total of 104 patients (age 72±8 years, 30% women) with calcific aortic valve disease, therefore predisposed to MAC, underwent 18F-sodium fluoride (calcification activity) and 18F-Fluorodeoxyglucose (18F-FDG, inflammation activity) PET, CT calcium scoring and echocardiography. Sixty patients underwent repeat CT and echocardiography after 2 years. RESULTS: MAC (mitral annular calcium score >0) was present in 35 (33.7%) patients who had increased 18F-fluoride (tissue-to-background ratio [TBR(max)] 2.32 [95% confidence interval 1.81-3.27]) vs. 1.30 [1.22-1.49], p

Arterial calcium deposition occurs in response to a spectrum of inflammatory and degenerative processes. Hydroxyapatite crystals are the building blocks of vascular calcification and are laid down as an early feature. This microcalcification exhibits a distinct biological profile from established calcified plaque, which is often the marker of quiescent disease. Detecting microcalcification offers great promise because it is associated with intense biological activity within the vascular bed and increased plaque vulnerability. Established imaging techniques, such as computed tomography, cannot identify microcalcification because it occurs at an extremely small scale. 18F-sodium fluoride is a biological radiotracer that binds to exposed hydroxyapatite crystals and can be detected using positron emission tomography (PET). 18F-sodium fluoride PET identifies microcalcification associated with high-risk atherosclerotic plaques that would otherwise require invasive imaging to be detected. Anatomical imaging is already an essential tool to stratify the risk of future cardiovascular events caused by calcifying disease. Combining these imaging techniques with the molecular insights of 18F-sodium fluoride PET offers a comprehensive assessment of vascular calcification. Together, this combination of structural and molecular assessment represents the next major paradigm in cardiovascular imaging and risk stratification.

BACKGROUND: Lipoprotein(a) [Lp(a)], a major carrier of oxidized phospholipids (OxPL), is associated with an increased incidence of aortic stenosis (AS). However, it remains unclear whether elevated Lp(a) and OxPL drive disease progression and are therefore targets for therapeutic intervention.OBJECTIVES: This study investigated whether Lp(a) and OxPL on apolipoprotein B-100 (OxPL-apoB) levels are associated with disease activity, disease progression, and clinical events in AS patients, along with the mechanisms underlying any associations.METHODS: This study combined 2 prospective cohorts and measured Lp(a) and OxPL-apoB levels in patients with AS (Vmax >2.0 m/s), who underwent baseline 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), repeat computed tomography calcium scoring, and repeat echocardiography. In vitro studies investigated the effects of Lp(a) and OxPL on valvular interstitial cells.RESULTS: Overall, 145 patients were studied (68% men; age 70.3 ± 9.9 years). On baseline positron emission tomography, patients in the top Lp(a) tertile had increased valve calcification activity compared with those in lower tertiles (n = 79; 18F-NaF tissue-to-background ratio of the most diseased segment: 2.16 vs. 1.97; p = 0.043). During follow-up, patients in the top Lp(a) tertile had increased progression of valvular computed tomography calcium score (n = 51; 309 AU/year [interquartile range: 142 to 483 AU/year] vs. 93 AU/year [interquartile range: 56 to 296 AU/year; p = 0.015), faster hemodynamic progression on echocardiography (n = 129; 0.23 ± 0.20 m/s/year vs. 0.14 ± 0.20 m/s/year] p = 0.019), and increased risk for aortic valve replacement and death (n = 145; hazard ratio: 1.87; 95% CI: 1.13 to 3.08; p = 0.014), compared with lower tertiles. Similar results were noted with OxPL-apoB. In vitro, Lp(a) induced osteogenic differentiation of valvular interstitial cells, mediated by OxPL and inhibited with the E06 monoclonal antibody against OxPL.CONCLUSIONS: In patients with AS, Lp(a) and OxPL drive valve calcification and disease progression. These findings suggest lowering Lp(a) or inactivating OxPL may slow AS progression and provide a rationale for clinical trials to test this hypothesis.

We assessed whether non-calcific low-density plaque on coronary CT angiography (CCTA) might improve risk stratification independent of classic risk markers. In the multicenter SCOT-HEART randomized controlled trial, we investigated associations between the risk of fatal or non-fatal myocardial

We assessed the feasibility of utilizing previously acquired computed tomography angiography (CTA) with subsequent positron-emission tomography (PET)-only scan for the quantitative evaluation ofForty-five patients (age 67.1±6.9 years; 76% males) underwent CTA (CTA1) and combinedCoronary CTA/PET protocol with CTA first followed by PET-only allows for reliable and reproducible quantification of

This study aimed to assess the association between increased lesion peri-coronary adipose tissue (PCAT) density and coronaryCoronaryPatients who underwent coronary CTA were screened for HRP, which was defined by 3 concurrent plaque features: positive remodeling; low attenuation plaque (LAP) (30 Hounsfield units [HU]) and spotty calcification; and obstructive coronary stenosis ≥50% (plaque volume100 mmForty-one patients (age 65 ± 6 years; 68% men) were recruited. Fifty-one lesions in 23 patients (56%) showed increased coronaryIn patients with HRP features on coronary CTA, increased density of PCAT was associated with focal

Bioprosthetic aortic valve degeneration is increasingly common, often unheralded, and can have catastrophic consequences.The authors sought to assess whetherExplanted degenerate bioprosthetic valves were examined ex vivo. Patients with bioprosthetic aortic valves were recruited into 2 cohorts with and without prosthetic valve dysfunction and underwent in vivo contrast-enhanced CT angiography,All ex vivo, degenerate bioprosthetic valves displayed