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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).

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.

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 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.

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.

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

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

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

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

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.

To evaluate the effect of age and aortic valve anatomy (tricuspid (TAV) vs bicuspid (BAV) aortic valve) on the relationship between the aortic valve calcification (AVC) and the haemodynamic parameters of aortic stenosis (AS) severity.Two hundred patients with AS and preserved left ventricular ejection fraction were prospectively recruited in the PROGRESSA (Metabolic Determinants of the Progression of Aortic Stenosis) study and underwent a comprehensive Doppler echocardiography and multidetector CT (MDCT). Mean transvalvular gradient (MG) measured by Doppler echocardiography was used to assess AS haemodynamic severity and AVC was evaluated by MDCT using the Agatston method and indexed to the left ventricular outflow tract area to obtain AVC density (AVCd). All analyses were adjusted for sex.Thirty-nine patients had a BAV and 161 a TAV. Median age was 51 and 72 years for BAV and TAV patients, respectively. There was a modest correlation between MG and AVCd (ρ=0.51, p0.0001) in the whole cohort. After dichotomisation for valve anatomy, there was a good correlation between AVCd and MG in the TAV group (ρ=0.61, p0.0001) but weak correlation in the BAV group (ρ=0.32, p=0.046). In the TAV group, the strength of the AVCd-MG correlation was similar in younger (72 years old; ρ=0.59, p0.0001) versus older (≥72 years old; ρ=0.61, p0.0001) patients. In the BAV group, there was no correlation between AVCd and MG in younger patients (51 years old; ρ=0.12, p=0.65), whereas there was a good correlation in older patients (≥51 years old; ρ=0.55, p=0.009). AVCd (p=0.005) and age (p=0.02) were both independent determinants of MG in BAV patients while AVCd (p0.0001) was the only independent determinant of MG in TAV patients.In patients with TAV as well as in older patients with BAV, AVCd appears to be the main factor significantly associated with the haemodynamic severity of AS and so it may be used to corroborate AS severity in case of uncertain or discordant findings at echocardiography. However, among younger patients with BAV, some may have a haemodynamically significant stenosis with minimal AVCd. The results of MDCT AVCd should thus be interpreted cautiously in this subset of patients.NCT01679431; Pre-results.