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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).

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Background Discordant echocardiographic measurements are observed in up to one third of patients with aortic stenosis (AS), in whom computed tomography (CT) derived aortic valve calcium scoring is now recommended. Nonetheless, CT calcium scoring only evaluates calcific valve thickening and is unable to assess non-calcific fibrotic thickening, which could be a relevant contributor of AS. Aim of the present study was to generate a quick and robust contrast-CT method based on a gaussian mixture model (GMM) for the assessment of fibro-calcific aortic valve thickening in AS patients, and to investigate its reproducibility and associations with echocardiographic parameters of AS severity and disease progression. Methods A post-hoc analysis of 136 patients with calcific AS (24 with severe, 81 moderate and 31 mild AS) enrolled in the SALTIRE2 trial (Study Investigating the Effects of Drugs used to Treat Osteoporosis on the Progression of Aortic Stenosis) (NCT-02132026) was performed. Aortic valve fibrocalcific volume was calculated using a GMM applied on contrast-CT at baseline and at 1-year follow up. The software estimated the Hounsfield Units (HU) distribution of 3 compartments (blood pool, non-calcific and calcific tissue) within the aortic valve volume of interest, automatically generating thresholds for non-calcific and calcific volumes, respectively computed as the lower 99.7 and the upper 99.7 percentile of the blood pool HU distribution (Figure). Thus, Fibrocalcific volume was measured as the sum of non-calcific and calcific volumes, indexed for CT annulus area and compared to echo parameters of AS severity. Scan-rescan reproducibility and analysis of AS progression were also assessed. Results Image analysis took 5.8 ± 1.0 minutes per scan and showed excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -9% to 7%). Indexed-fibrocalcific volume correlated well with echocardiographic aortic peak velocity (rho=0.70, p Conclusions This contrast CT-based approach based on a GMM is able to provide robust and relatively rapid assessment of fibrocalcific thickening in patients with AS. Fibrocalcific volume measured using this method, correlates well with other markers of AS severity, predicts disease progression and holds promise in tracking disease progression and response to novel therapies.

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 The authors explored the development and validation of machine-learning models for augmenting the echocardiographic grading of aortic stenosis (AS) severity. Background In AS, symptoms and adverse events develop secondarily to valvular obstruction and left ventricular decompensation. The current echocardiographic grading of AS severity focuses on the valve and is limited by diagnostic uncertainty. Methods Using echocardiography (ECHO) measurements (ECHO cohort, n = 1,052), we performed patient similarity analysis to derive high-severity and low-severity phenogroups of AS. We subsequently developed a supervised machine-learning classifier and validated its performance with independent markers of disease severity obtained using computed tomography (CT) (CT cohort, n = 752) and cardiovascular magnetic resonance (CMR) imaging (CMR cohort, n = 160). The classifier’s prognostic value was further validated using clinical outcomes (aortic valve replacement [AVR] and death) observed in the ECHO and CMR cohorts. Results In 1,964 patients from the 3 multi-institutional cohorts, 1,346 (68%) subjects had either nonsevere or discordant AS severity. Machine learning identified 1,117 (57%) patients as having high-severity and 847 (43%) as having low-severity AS. High-severity patients in CT and CMR cohorts had higher valve calcium scores and left ventricular mass and fibrosis, respectively than the low-severity group. In the ECHO cohort, progression to AVR and progression to death in patients who did not receive AVR was faster in the high-severity group. Compared with the conventional classification of disease severity, machine-learning–based severity classification improved discrimination (integrated discrimination improvement: 0.07; 95% confidence interval: 0.02 to 0.12) and reclassification (net reclassification improvement: 0.17; 95% confidence interval: 0.11 to 0.23) for the outcome of AVR at 5 years. For both ECHO and CMR cohorts, we observed prognostic value of the machine-learning classifications for subgroups with asymptomatic, nonsevere or discordant AS. Conclusions Machine learning can integrate ECHO measurements to augment the classification of disease severity in most patients with AS, with major potential to optimize the timing of AVR.

Background Discordant echocardiography is observed in up to one third of patients with aortic stenosis (AS), in whom computed tomography (CT) derived aortic valve calcium scoring is now recommended. However, CT calcium scoring only assesses calcific valve thickening and ignores non-calcific fibrotic thickening, which could be an important contributor of AS. Purpose To generate a quick and robust contrast-CT method based on a gaussian mixture model (GMM) for assessment of fibro-calcific aortic valve thickening in patients with AS, and to investigate its reproducibility and associations with echo parameters of AS severity and disease progression. Methods A post-hoc analysis of 136 patients with calcific AS (24 with severe, 81 moderate and 31 mild AS) enrolled in the SALTIRE2 trial (NCT-02132026) was performed. Aortic valve fibrocalcific volume was calculated using a GMM applied on contrast-CT at baseline and at 1-year follow up. The software estimated the Hounsfield Units (HU) distribution of 3 compartments (blood pool, non-calcific and calcific tissue) within the aortic valve volume of interest, automatically generating thresholds for non-calcific and calcific tissue, respectively computed as the lower 99.7 and the upper 99.7 percentile of the blood pool HU distribution (Figure 1). Fibrocalcific volume was measured as the sum of calcific and non-calcific volumes, indexed for CT annulus area and compared to echo parameters of AS severity. Evaluation of scan-rescan reproducibility and AS progression were also assessed. Results Image analysis took 5.8±1.0 minutes per scan and showed excellent scan-rescan reproducibility (mean difference −1%, limits of agreement −9% to 7%). Indexed-fibrocalcific volume correlated well with echocardiographic aortic peak velocity (rho=0.70, p Conclusions This novel contrast CT-based approach can provide robust and rapid assessment of fibrocalcific thickening in AS patients. Fibrocalcific volume measured using this technique, correlates well with other markers of AS severity, predicts disease progression and holds promise in tracking disease progression and response to novel therapies. Funding Acknowledgement Type of funding sources: None.

Background: Sex-specific thresholds of computed tomography (CT)-derived aortic valve calcification (AVC) or AVC density (AVCd) to identify severe aortic stenosis (AS) have been established in populations that consisted mainly of Caucasians with a tricuspid aortic valve. The objective of this study was to evaluate the accuracy (i.e., sensitivity and specificity) of previously established thresholds to identify severe AS in patients with bicuspid aortic valve (BAV) and according to ethnicity: Caucasian vs. Asian. Methods: We built a multicenter registry of echocardiographic and CT data collected in BAV patients with at least mild AS and preserved left ventricular ejection fraction from 7 different centers. Anatomic severity of AS obtained by CT-derived AVC and AVCd was compared to hemodynamic severity of AS obtained by echocardiography. Results: Among 485 BAV patients (60% men, 73% Asians), the best thresholds of AVC and AVCd to identify severe AS in BAV patients were 2315 arbitrary units (AU) (sensitivity [Se]/specificity [Spe] = 82/78%) in men, 1103 AU (Se/Spe = 80/82%) in women, and 561 AU/cm2 (Se/Spe = 86/91%) in men, and 301 AU/cm2 (Se/Spe = 83/ 82%) in women, respectively. According to ethnicity, thresholds for severe AS in Caucasian patients were, respectively, in men and women: 2208 AU (Se/Spe = 83/83%) and 1230 AU (Se/Spe = 87/82%) for AVC and 474 AU/cm2 (Se/Spe = 88/83%) and 358 AU/cm2 (Se/Spe = 80/82%) for AVCd. In Asian patients, they were 2582 AU (Se/Spe = 76/78%) and 924 AU (Se/Spe = 84/80%) for AVC and 640 AU/cm2 (Se/Spe = 82/89%) and 255 AU/cm2 (Se/Spe = 86/80%) for AVCd. Conclusions: The optimal thresholds to identify hemodynamically severe AS in BAV patients are similar in Caucasians but appear to be higher in Asian men, compared with thresholds previously reported in tricuspid aortic valve patients. Nonetheless, the thresholds currently proposed in the guidelines have good accuracy and can be applied in BAV patients to confirm AS severity.

Background: Pericoronary adipose tissue (PCAT) attenuation and low-attenuation noncalcified plaque (LAP) burden can both predict outcomes. Objectives: This study sought to assess the relative and additive values of PCAT attenuation and LAP to predict future risk of myocardial infarction. Methods: In a post hoc analysis of the multicenter SCOT-HEART (Scottish Computed Tomography of the Heart) trial, the authors investigated the relationships between the future risk of fatal or nonfatal myocardial infarction and PCAT attenuation measured from coronary computed tomography angiography (CTA) using multivariable Cox regression models including plaque burden, obstructive coronary disease, and cardiac risk score (incorporating age, sex, diabetes, smoking, hypertension, hyperlipidemia, and family history). Results: In 1,697 evaluable participants (age: 58 ± 10 years), there were 37 myocardial infarctions after a median follow-up of 4.7 years. Mean PCAT was −76 ± 8 HU and median LAP burden was 4.20% (IQR: 0%-6.86%). PCAT attenuation of the right coronary artery (RCA) was predictive of myocardial infarction (HR: 1.55; P = 0.017, per 1 SD increment) with an optimum threshold of −70.5 HU (HR: 2.45; P = 0.01). In multivariable analysis, adding PCAT-RCA of ≥−70.5 HU to an LAP burden of >4% (the optimum threshold for future myocardial infarction; HR: 4.87; P < 0.0001) led to improved prediction of future myocardial infarction (HR: 11.7; P < 0.0001). LAP burden showed higher area under the curve compared to PCAT attenuation for the prediction of myocardial infarction (AUC = 0.71 [95% CI: 0.62-0.80] vs AUC = 0.64 [95% CI: 0.54-0.74]; P < 0.001), with increased area under the curve when the 2 metrics are combined (AUC = 0.75 [95% CI: 0.65-0.85]; P = 0.037). Conclusion: Coronary CTA–defined LAP burden and PCAT attenuation have marked and complementary predictive value for the risk of fatal or nonfatal myocardial infarction.

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

To assess the prognostic implications of standardized reporting systems for coronary computed tomography angiography (CCTA) and coronary artery calcium scores (CACS) in patients with stable chest pain.The Coronary Artery Disease Reporting And Data System (CAD-RADS) and Coronary Artery Calcium - Data and Reporting System (CAC-DRS) aim to improve communication of CACS and CCTA results, but its influence on prognostication is unknown.Images from 1769 patients who underwent CCTA as part of the Scottish Computed Tomography of the HEART (SCOT-HEART) multi-center randomized controlled trial were assessed. CACS were classified as CAC-DRS 0 to 3 based on Agatston scores. CCTA were classified as CAD-RADS 0 to 5 based on the most clinically relevant finding per patient. The primary outcome was the five-year events of fatal and non-fatal myocardial infarction.Patients had a mean age of 58 ± 10 years and 56% were male. CAC-DRS 0, 1, 2 and 3 occurred in 642 (36%), 510 (29%), 239 (14%) and 379 (21%) patients respectively. CAD-RADS 0, 1, 2, 3, 4A, 4B and 5 occurred in 622 (35%), 327 (18%), 211 (12%), 165 (9%), 221 (12%), 42 (2%) and 181 (10%) patients respectively. Patients classified as CAC-DRS 3 were at an increased risk of fatal or non-fatal myocardial infarction compared to CAC-DRS 0 patients (hazard ratio (HR) 9.41; 95% confidence interval (CI) 3.24, 27.31; p 0.001). Patients with higher CAD-RADS categories were at an increased risk of fatal or non-fatal myocardial infarction, with patients classified as CAD-RADS 4B at the highest risk compared to CAD-RADS 0 patients (HR 19.14; 95% CI 4.28, 85.53; p 0.001).Patients with higher CAC-DRS and CAD-RADS scores were at increased risk of subsequent fatal and non-fatal myocardial infarction. This confirms that the classification provides additional prognostic discrimination for future coronary heart disease events.

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.

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.

Aims Sex-specific thresholds of aortic valve calcification (AVC) have been proposed and validated in Caucasians. Thus, we aimed to validate their accuracy in Asians. Methods and results Patients with calcific aortic stenosis (AS) from seven international centres were included. Exclusion criteria were ≥moderate aortic/mitral regurgitation and bicuspid valve. Optimal AVC and AVC-density sex-specific thresholds for severe AS were obtained in concordant grading and normal flow patients (CG/NF). We included 1263 patients [728 (57%) Asians, 573 (45%) women, 837 (66%) with CG/NF]. Mean gradient was 48 (26–64) mmHg and peak aortic velocity 4.5 (3.4–5.1) m/s. Optimal AVC thresholds were: 2145 Agatston Units (AU) in men and 1301 AU in women for Asians; and 1885 AU in men and 1129 AU in women for Caucasians. Overall, accuracy (% correctly classified) was high and comparable either using optimal or guidelines’ thresholds (2000 AU in men, 1200 AU in women). However, accuracy was lower in Asian women vs. Caucasian women (76–78% vs. 94–95%; P 0.41) with regards to AS haemodynamic severity. Conclusion AVC thresholds defining severe AS are comparable in Asian and Caucasian populations, and similar to those proposed in the guidelines. However, accuracy of AVC to identify severe AS in Asians (especially women) is sub-optimal. Therefore, the use of AVC-density is preferable in Asians.

The first-line evaluation of aortic stenosis severity is Doppler echocardiography. However, in up to 40% of patients, resting echocardiographic assessment of aortic stenosis severity is discordant, leading to clinical uncertainty. Interest has therefore grown in aortic valve calcium scoring by multidetector computed tomography (CT-AVC) as an alternative load independent assessment of aortic stenosis severity. This paper will briefly review the pathophysiology of aortic stenosis and the crucial role that calcification plays in driving progressive obstruction of the valve. Subsequently, it will describe published reports that have investigated CT-AVC, validating this parameter against histology, and establishing its diagnostic accuracy versus echocardiography as well as its powerful independent prognostic capability. Finally, this review seeks to provide a practical guide about how best to acquire and interpret CT-AVC with a close focus on potential pitfalls and how these might be best avoided as this technique becomes more widely adopted in to clinical practice.

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).

Aims Valvular heart disease can be identified by calcification on coronary computed tomography angiography (CCTA) and has been associated with adverse clinical outcomes. We assessed aortic and mitral valve calcification in patients presenting with stable chest pain and their association with cardiovascular risk factors, coronary artery disease, and cardiovascular outcomes. Methods and results In 1769 patients (58 ± 9 years, 56% male) undergoing CCTA for stable chest pain, aortic and mitral valve calcification were quantified using Agatston score. Aortic valve calcification was present in 241 (14%) and mitral calcification in 64 (4%). Independent predictors of aortic valve calcification were age, male sex, hypertension, diabetes mellitus, and cerebrovascular disease, whereas the only predictor of mitral valve calcification was age. Patients with aortic and mitral valve calcification had higher coronary artery calcium scores and more obstructive coronary artery disease. The composite endpoint of cardiovascular mortality, non-fatal myocardial infarction, or non-fatal stroke was higher in those with aortic [hazard ratio (HR) 2.87; 95% confidence interval (CI) 1.60–5.17; P Conclusion Aortic and mitral valve calcification occurs in one in six patients with stable chest pain undergoing CCTA and is associated with concomitant coronary atherosclerosis. Whilst valvular calcification is associated with a higher risk of cardiovascular events, this was not independent of the burden of coronary artery disease.

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.

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 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

Aims The relative benefits of computed tomography coronary angiography (CTCA)-guided management in women and men with suspected angina due to coronary heart disease (CHD) are uncertain. Methods and results In this post hoc analysis of an open-label parallel-group multicentre trial, we recruited 4146 patients referred for assessment of suspected angina from 12 cardiology clinics across the UK. We randomly assigned (1:1) participants to standard care alone or standard care plus CTCA. Fewer women had typical chest pain symptoms (n = 582, 32.0%) when compared with men (n = 880, 37.9%; P Conclusion Following the addition of CTCA, women were more likely to be found to have normal coronary arteries than men. This led to more women being reclassified as not having CHD, resulting in more downstream tests and treatments being cancelled. There were similar prognostic benefits of CTCA for women and men.

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

Background— Computed tomography aortic valve calcium scoring (CT-AVC) holds promise for the assessment of patients with aortic stenosis (AS). We sought to establish the clinical utility of CT-AVC in an international multicenter cohort of patients. Methods and Results— Patients with AS who underwent ECG-gated CT-AVC within 3 months of echocardiography were entered into an international, multicenter, observational registry. Optimal CT-AVC thresholds for diagnosing severe AS were determined in patients with concordant echocardiographic assessments, before being used to arbitrate disease severity in those with discordant measurements. In patients with long-term follow-up, we assessed whether CT-AVC thresholds predicted aortic valve replacement and death. In 918 patients from 8 centers (age, 77±10 years; 60% men; peak velocity, 3.88±0.90 m/s), 708 (77%) patients had concordant echocardiographic assessments, in whom CT-AVC provided excellent discrimination for severe AS (C statistic: women 0.92, men 0.89). Our optimal sex-specific CT-AVC thresholds (women 1377 Agatston unit and men 2062 Agatston unit) were nearly identical to those previously reported (women 1274 Agatston unit and men 2065 Agatston unit). Clinical outcomes were available in 215 patients (follow-up 1029 [126–2251] days). Sex-specific CT-AVC thresholds independently predicted aortic valve replacement and death (hazard ratio, 3.90 [95% confidence interval, 2.19–6.78]; P P =0.010). Conclusions— Sex-specific CT-AVC thresholds accurately identify severe AS and provide powerful prognostic information. These findings support their integration into routine clinical practice. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifiers: NCT01358513, NCT02132026, NCT00338676, NCT00647088, NCT01679431.

Aortic stenosis is a common, potentially fatal condition that is set to become an increasing public health burden. Once symptoms develop, there is an inexorable deterioration with a poor prognosis. Despite this, there are no medical therapies capable of modifying disease progression, and the only available treatment is aortic valve replacement, to which not all patients are suited. Conventional teaching suggests that aortic stenosis is a degenerative condition whereby "wear and tear" leads to calcium deposition within the valve. Although mechanical stress and injury are important factors, it is becoming increasingly appreciated that aortic stenosis is instead governed by a highly complex, regulated pathological process with similarities to skeletal bone formation. This review discusses the pathophysiology of aortic stenosis with an emphasis on the emerging importance of calcification, how this can be visualized and monitored using noninvasive imaging, and how our improved knowledge may ultimately translate into novel disease-modifying treatments.

ObjectivesTo evaluate the diagnostic and prognostic benefits of CT coronary angiography (CTCA) using the 2016 National Institute for Health and Care Excellence (NICE) guidelines for the assessment of suspected stable angina.MethodsPost hoc analysis of the Scottish COmputed Tomography of the HEART (SCOT-HEART) trial of 4146 participants with suspected angina randomised to CTCA. Patients were dichotomised into NICE guideline-defined possible angina and non-anginal presentations. Primary (diagnostic) endpoint was diagnostic certainty of angina at 6 weeks and prognostic endpoint comprised fatal and non-fatal myocardial infarction (MI).ResultsIn 3770 eligible participants, CTCA increased diagnostic certainty more in those with possible angina (relative risk (RR) 2.22 (95% CI 1.91 to 2.60), pinteraction ConclusionsNICE-guided patient selection maximises the benefits of CTCA on diagnostic certainty, use of invasive coronary angiography and reductions in fatal and non-fatal myocardial infarction. Patients with non-anginal chest pain derive minimal benefit from CTCA and increase the rates of invasive investigation.Trial registration numberClinicalTrials.gov: NCT01149590;post results.

A 38-year-old man was admitted with vasculitic rash and horizontal diplopia 9 months post allogenic stem cell transplantation for T-cell acute lymphoblastic leukemia (ALL). Magnetic resonance (MR) of the orbits showed enlarged extra-ocular muscles and an echocardiogram, to exclude cardiac embolic sources, showed bi-ventricular hypertrophy and speckled myocardium. A 12-lead ECG showed diffuse T-wave …

18F-NaF PET CT can image aortic valve and coronary artery microcalcification. With reduced radiation exposure PET MR may be favoured over PET CT but concern remains over the accuracy of attenuation correction (AC) maps. We compared 18F-NaF uptake across PET CT and PET MR using breath held, free

Pulmonary hypertension (PH) is a major cause of morbidity and mortality, but it often presents with nonspecific symptoms, thereby delaying diagnosis and treatment. While invasive cardiac catheterization is essential to confirm the diagnosis, patients with breathlessness are commonly encountered in clinical practice creating a demand for noninvasive screening methods. Preliminary investigations such as the electrocardiogram and chest radiograph lack sensitivity even in advanced cases. Echocardiography is used to screen patients; however, over-reliance on a single estimation of pulmonary artery systolic pressure is unwise, instead multiple parameters should be assessed. Once a diagnosis of PH is made, radionuclide imaging should be performed to exclude chronic thromboembolic disease, and computed tomography is vital for eliminating parenchymal lung disease as a potential etiology. Currently, the primary contribution of cardiac MRI is the accurate assessment of right ventricular size and function. In this respect, cardiac MRI may be supportive during diagnosis of PH, but the main importance of this is in defining prognosis although new outcome variables are anticipated.

Background Patients with complex congenital heart disease associated with tracheobronchomalacia (TBM) remain difficult to manage after cardiac surgery. We studied the influence of TBM on the outcomes of pediatric patients after cardiac surgery for congenital heart disease to determine how to manage these patients better. Methods Twenty-two consecutive pediatric patients who had TBM diagnosed by bronchoscopy or dynamic contrast bronchography before or after cardiac surgery for congenital heart disease during a 5.5-year period were compared with an age- and procedure-matched control group operated on during the same period. Patients diagnosed postoperatively were investigated after a second failed extubation. Patients were managed by oxygen administration, endotracheal suctioning, and positive end-expiratory or continuous positive airway pressure through a nasotracheal tube or tracheostomy. Results There were 4 deaths within 1 year of surgery, all in the study group, with 2 early (neither of which appeared related to TBM) and 2 late. The estimated survival at 5 years was 82% (95% confidence interval, 59% to 93%) for the study group compared with 100% for control patients (p = 0.012). All deaths occurred in patients undergoing palliative procedures (p = 0.0004), and both children who underwent redo operations died (p = 0.02). Postoperatively, 50% of children with TBM required prolonged ventilation and tracheostomy. Compared with control patients the average postoperative ventilation time, pediatric intensive care unit stay, and hospital stay were 6.5, 11.5, and 20 days versus 1, 2, and 6.5 days, respectively (p Conclusions Although associated with longer postoperative ventilation time, pediatric intensive care unit stay, hospital stay, and mortality, outcomes after cardiac procedures in children with TBM are acceptable. Palliative and redo procedures in this group of patients are associated with significantly higher risk of death.

The prevalence of calcific aortic stenosis increases with age, occurring in 3% to 5% of individuals aged >75 years.1,2 The narrowing of the aortic valve is driven by a highly complex and intricately regulated process of inflammation, fibrosis, and calcification, which eventually results in leaflet immobility and the associated hemodynamic consequences.3 In response to the narrowed valve, left ventricular hypertrophy is initially adaptive to restore wall stress and cardiac performance. Ultimately, adverse events, such as symptoms, heart failure, and death, occur as the left ventricle decompensates. This transition from adaptation to decompensation is driven by progressive myocyte death and myocardial fibrosis.4–6 Therefore, it is important to consider aortic stenosis as a condition that affects both the valve and the myocardium.5,6 Indeed, contemporary guidelines recommend aortic valve replacement in patients with severe aortic stenosis and evidence of advanced ventricular decompensation, defined by either the presence of symptoms or an impaired systolic ejection fraction

Aortic stenosis is the major cause of valve disease in the Western world and a growing healthcare burden. We lack medication capable of slowing disease progression and so rely on aortic valve replacement in patients with severe disease and symptoms. Predicting when this will occur is challenging with the literature suggesting on average slow progression with wide individual variation (rate of change in the mean gradient of ∼3±3 mm Hg/year). Annual or biannual clinical review is therefore required in all patients with serial echocardiography performed in order to track progressive valve narrowing.1 This incurs significant costs and a method capable of predicting the future natural history of aortic stenosis and the likely timing of valve surgery could help streamline patient care. It is on this background that Nguyen et al 2 investigated whether an association exists between baseline aortic stenosis severity and the rate of disease progression. In 149 patients with largely mild and moderate disease, the average rate of haemodynamic progression after a mean follow-up of 2.9±1.0 years was again +3±3 mm Hg/year (mean gradient). As anticipated the fastest rates of progression were observed in those patients with the most advanced aortic stenosis …

The developing heart has a much greater dependence on amino acid (AA) metabolism than the adult heart in determining its ischemic tolerance. Blood cardioplegia preserves myocardial free AAs in adult hearts but no clinical studies have looked at the effect of different cardioplegic techniques on intracellular free AAs in the pediatric heart.Pediatric patients were randomised to receive intermittent antegrade cold crystalloid (CC), cold blood (CB) or cold blood cardioplegia with a 'hot shot' (CB+HS). Right ventricular biopsies were collected prior to ischemia, at the end of ischemia and 20 min after reperfusion. Amino acid levels were analysed as repeated measures, adjusting for baseline levels. Data were analysed separately for acyanotic and cyanotic patients.Of 103 patients recruited, 32 (22 acyanotic and 10 cyanotic), 36 (24/12) and 35 (25/10), respectively were allocated to CC, CB and CB+HS groups. Cyanotic patients were significantly younger with longer cross-clamp times. In acyanotic patients, there were no significant effects of cardioplegic method on aspartate, glutamine, taurine, alanine or branched chain AA levels (all p0.05). However, in cyanotic patients, there were significant interactions of cardioplegic method and time (all p0.05) for all amino acids, with patients allocated to CB+HS having higher levels after reperfusion compared with CC, and patients allocated to CB having intermediate levels.For cyanotic patients (younger, longer cross-clamp times), CB+HS preserves myocardial free AAs better than CC; CB gives an intermediate effect. In acyanotic patients, AA levels (all p0.15) and group means were similar both at the end of ischemia and after reperfusion.

There is little evidence in the literature on the benefits of cold blood cardioplegia in pediatric cardiac surgery. This study investigates the effects of cold crystalloid versus cold blood cardioplegia on myocardial metabolism, reperfusion injury, and clinical outcomes in patients undergoing ventricular septal defect (VSD) repair.Patients were randomly assigned to receive antegrade cold (4 to 6 degrees C) St Thomas's I crystalloid (CCC) or blood (CBC) cardioplegia. Changes in myocardial adenine nucleotides and purine levels were monitored in right ventricular biopsies and postoperative serum troponin I (TnI) and lactate release were measured.Forty patients were randomly assigned to CCC (n = 21; age 21.1 +/- 40.8 months) or to CBC (n = 19; age 27.4 +/- 39.3 months). Patient characteristics were similar in the two groups and there was no mortality. After the ischemic period there was a significant drop in adenosine triphosphate levels compared with control values in the CCC (40.4 +/- 9.9 versus 27.5 +/- 12.5 nmol/mg protein, p = 0.01) but not in the CBC group (40.3 +/- 23.2 versus 37.3 +/- 18.9 nmol/mg protein). The fall was more marked in infants compared with children (40% versus 10%, respectively, p = 0.01). Mean total TnI release was 42% lower in the CBC than the CBC group (95% confidence interval 10% to 62%, p = 0.015). Total TnI release was significantly associated with age (p0.001) but as levels in infants in the CBC group were the same as for children, the reduction with age was seen almost entirely in the CCC group. There were no differences in the duration of inotropic support, ventilation time, intensive care unit, or hospital stay in the two groups.The use of CBC is associated with less metabolic myocardial ischemic stress and reperfusion injury when compared with CCC in pediatric patients undergoing VSD repair.

Background: High-sensitivity assays can quantify cardiac troponin I (hs-cTnI) concentrations in nearly all individuals. We determined whether hs-cTnI could improve estimates of the pre-test probability of obstructive coronary artery disease (CAD) in patients with suspected stable angina. Methods

Introduction: Urocortin 2 (UCN 2) and urocortin 3 (UCN 3) are endogenous peptide hormones with an emerging role in the pathophysiology and treatment of heart failure. For the first time, we examined the systemic cardiovascular effects of both UCN 2 and UCN 3 in healthy volunteers and patients with heart failure. Methods: Seven healthy volunteers (Group A) and nine patients with stable chronic heart failure (Group B, New York Heart Association class II and III, left ventricular ejection fraction Results: Other than diastolic blood pressure (78 vs 72 mmHg for Group A and B respectively, p0.05 for all). SNP, UCN2 and UCN 3 infusions increased heart rate and cardiac index, and reduced systolic and diastolic blood pressure and peripheral vascular resistance index (PVRI) in both healthy volunteers and patients with heart failure (p0.05). Conclusion: Intravenous UCN 2 and especially UCN 3 increase cardiac output and reduce peripheral vascular resistance. This favourable haemodynamic profile suggests that UCN 2 and UCN 3 hold exciting therapeutic potential for the treatment of acute heart failure.