Aortic stenosis (AS) is characterized by calcification and fibrosis. The ability to quantify these processes simultaneously has been limited with previous imaging methods. The purpose of this study was to evaluate the aortic valve fibrocalcific volume by computed tomography (CT) angiography in patients with AS, in particular, to assess its reproducibility, association with histology and disease severity, and ability to predict/track progression. In 136 patients with AS, fibrocalcific volume was calculated on CT angiograms at baseline and after 1 year. CT attenuation distributions were analyzed using Gaussian-mixture-modeling to derive thresholds for tissue types enabling the quantification of calcific, noncalcific, and fibrocalcific volumes. Scan-rescan reproducibility was assessed and validation provided against histology and in an external cohort. Fibrocalcific volume measurements took 5.8 ± 1.0 min/scan, demonstrating good correlation with ex vivo valve weight (r = 0.51; P < 0.001) and excellent scan-rescan reproducibility (mean difference -1%, limits of agreement -4.5% to 2.8%). Baseline fibrocalcific volumes correlated with mean gradient on echocardiography in both male and female participants (rho = 0.64 and 0.69, respectively; both P < 0.001) and in the external validation cohort (n = 66, rho = 0.58; P < 0.001). The relationship was driven principally by calcific volume in men and fibrotic volume in women. After 1 year, fibrocalcific volume increased by 17% and correlated with progression in mean gradient (rho = 0.32; P = 0.003). Baseline fibrocalcific volume was the strongest predictor of subsequent mean gradient progression, with a particularly strong association in female patients (rho = 0.75; P < 0.001). The aortic valve fibrocalcific volume provides an anatomic assessment of AS severity that can track disease progression precisely. It correlates with disease severity and hemodynamic progression in both male and female patients.

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

Background Inflammation plays a pivotal role in atherogenesis and is a causal risk factor for atherosclerotic cardiovascular disease. Non-invasive coronary CT angiography (CCTA) enables evaluation of coronary plaque phenotype. This study investigates the relationship between a comprehensive panel of inflammatory markers and short-term plaque progression on serial CCTA imaging, hypothesising that inflammation is associated with increased plaque volume. Methods A total of 161 patients aged ≥40 years with stable multivessel coronary artery disease were included, who underwent CCTA at baseline and 12 months follow-up. Baseline plasma levels of interleukin 6 (IL-6), high-sensitivity C-reactive protein and other inflammatory markers were measured. Plaque volumes were assessed using semiautomated software, calculating total, noncalcified, calcified and low-attenuation noncalcified plaque volumes. Linear regression models, adjusted for ASSIGN score, segment involvement score and body mass index, evaluated associations between inflammatory markers and plaque volume changes. Results The mean±SD age was 65.4±8.4 years, with 129 (80.6%) male participants. Baseline total plaque volume was 1394 (1036, 1993) mm³. After 12 months, total plaque volume changed by 78 (−114, 244) mm³. IL-6 levels were associated with a 4.9% increase in total plaque volume (95% CI: 0.9 to 8.9, p=0.018) and a 4.8% increase in noncalcified plaque volume (95% CI: 0.7 to 8.9, p=0.022). No significant associations were observed for other inflammatory markers. Conclusions Plasma IL-6 levels are significantly associated with increased total and noncalcified short-term plaque progression in patients with stable coronary artery disease. This supports the potential of IL-6 as a target for reducing plaque progression and cardiovascular risk.

BACKGROUND: Aortic stenosis (AS) involves calcific and fibrotic degeneration of the valve tissue. The only noninvasive method for evaluating both processes is contrast-enhanced computed tomography angiography. We aimed to explore the differences in aortic valve (AV) tissue composition across sex, race/ethnicity, and AS hemodynamic phenotype in US patients referred for transcatheter AV replacement planning. METHODS: We retrospectively analyzed symptomatic patients with AS who underwent computed tomography angiography for transcatheter AV replacement planning between 2015 and 2022. Using semi-automated software, we quantified the AV tissue composition by fibrotic, calcific, and fibro-calcific volumes, and the fibro-calcific ratio (fibrotic/calcific volume) as a measure of valve phenotype. RESULTS: The study included 651 patients (mean age 84 years; 55% women) with 38% non-Hispanic (NH)-White, 27% Hispanic, and 13% NH-Black. Women had lower fibro-calcific (230 versus 293 mm³/cm²; P <0.001) and calcific volumes (85 versus 149 mm³/cm²; P <0.001), and higher fibro-calcific ratio (1.47 versus 0.83; P <0.001). No differences were observed in the fibrotic volumes ( P =0.805). NH-White women had higher fibro-calcific (256 mm³/cm², P =0.002) and fibrotic volumes (145 mm³/cm²; P <0.001), and fibro-calcific ratio (1.57; P =0.01) compared with Hispanic and NH-Black women. No differences were found among men. High-gradient AS had higher fibro-calcific (295 versus 219 mm ³ /cm ² ; P <0.001) and calcific volumes (148 versus 88 mm ³ /cm ² ; P <0.001), and a lower fibro-calcific ratio (0.90 versus 1.45; P <0.001), although no difference in fibrotic volume ( P =0.099) compared with low-gradient AS. CONCLUSIONS: Phenotypic differences in computed tomography angiography valve tissue composition exist in patients with AS referred for transcatheter AV replacement, with women and low-gradient AS showing a proportionally more fibrotic phenotype. NH-White women have the highest fibrotic tissue composition, and no differences are evident among men.

Calcium scoring from noncontrast computed tomography (CT) is used clinically to adjudicate aortic stenosis severity in patients with discordant echocardiography. The aim of this study was to investigate whether quantification of aortic valve calcium volume from computed tomography angiography (CTA) can provide robust diagnostic discrimination of disease severity and inform risk stratification of patients with aortic stenosis. Patients with mild to severe aortic stenosis who underwent concurrent CTA and echocardiography were included in a retrospective international multicenter observational cohort study. Accuracy of aortic valve calcium volume to diagnose severe aortic stenosis in patients with concordant disease on echocardiography was assessed. Association of aortic valve calcium volume with the incidence of aortic valve replacement or all-cause death was investigated. The study included 1,521 patients (mean age: 74 ± 10 years; 44% female; median peak aortic jet velocity: 3.8 m/s [Q1-Q3: 3.1-4.5 m/s]). Indexed aortic valve calcium volume correlated with peak aortic jet velocity (ρ = 0.723; P < 0.001) and noncontrast CT calcium score (ρ = 0.896; P < 0.001). In the derivation cohort (n = 689), sex-specific thresholds for indexed calcium volume (men: 122 mm³/cm²; women: 61 mm³/cm²) provided excellent diagnostic discrimination for severe aortic stenosis (C-statistic: 0.900 for men; 0.926 for women). Similar diagnostic discrimination was observed in the validation cohort (n = 459; C-statistic: 0.933 for men; 0.944 for women). Clinical outcomes were available in 711 patients (25% with discordant echocardiography), with 249 reaching the primary endpoint after 26 months (Q1-Q3: 12-53 months). Indexed calcium volume thresholds were independently associated with aortic valve replacement or all-cause mortality in both the cohort as a whole (HR: 2.01 [95% CI: 1.30-3.10]; P < 0.01) and those with discordant echocardiography (HR: 1.58 [95% CI: 1.01-2.44]). In patients with aortic stenosis, indexed aortic valve calcium volume from CTA provides accurate discrimination of disease severity and additive prognostic information. This technique can be easily applied to patients undergoing CTA for transcatheter aortic valve replacement or coronary artery evaluation without the need for a separate noncontrast CT scan.