ABSTRACT
Geoacoustic inversion can be a computationally expensive task in high-dimensional parameter spaces, typically requiring thousands of forward model evaluations to estimate the geoacoustic environment. We demonstrate Bayesian optimization (BO), an efficient global optimization method capable of estimating geoacoustic parameters in seven-dimensional space within 100 evaluations instead of thousands. BO iteratively searches parameter space for the global optimum of an objective function, defined in this study as the Bartlett power. Each step consists of fitting a Gaussian process surrogate model to observed data and then choosing a new point to evaluate using a heuristic acquisition function. The ideal acquisition function balances exploration of the parameter space in regions with high uncertainty with exploitation of high-performing regions. Three acquisition functions are evaluated: upper confidence bound, expected improvement (EI), and logarithmically transformed EI. BO is demonstrated for both simulated and experimental data from a shallow-water environment and rapidly estimates optimal parameters while yielding results comparable to differential evolution optimization.
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BACKGROUND: Aortic-valve-stenosis (AS) is a frequent degenerative valvular-disease and carries dismal outcome under-medical-treatment. Transvalvular pressure gradient reflects severity of the valve-disease but is highly dependent on flow-conditions and on other valvular/aortic characteristics. Alternatively, aortic-valve-area (AVA) represents a measure of aortic-valve lesion severity conceptually essential and practically widely-recognized but exhibits multiple-limitations. METHODS: We analyzed the 4D multi-detector computed tomography(MDCT) of 20 randomly selected patients with severe AS. For each-patient, we generated the 3D-model of the valve and of its calcifications, and we computed the anatomical AVA accounting for the 3D-morphology of the leaflets in three-different-ways. Finally, we compared our results vs. Doppler-based AVAE measurements and vs. 2D-planimetric AVA-measurements. RESULTS: 3D-reconstruction and identification of the cusps were successful in 90% of the cases. The calcification patterns where highly-variable over patients, ranging from multiple small deposits to wide and c-shaped deposits running from commissure-to-commissure. AVAE was 82 ± 15 mm2. When segmenting 18 image planes, AVATight, AVAProj-Ann, AVAProj-Tip and their average AVAAve were equal to 80 ± 16, 88 ± 20, 93 ± 21 and 87 ± 19 mm2, respectively, while AVAPlan was equal to 143 ± 50 mm2. Linear-regression of the three measurements vs. AVAE yielded regression slopes equal to 1.26, 1.13 and 0.93 for AVAProj-Ann, AVAProj-Tip and AVATight, respectively. The respective Pearson-coefficients were 0.85,0.86 and 0.90. Conversely, when comparing AVAPlan vs. AVAE, linear regression yielded a slope of 1.73 and a Pearson coefficient of 0.53. CONCLUSIONS: We described a new-method to obtain a set of flow-independent quantifications that complement pressure gradient measurements and combine the advantages of previously proposed methods, while bypassing the corresponding-limitations.
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BACKGROUND: Cure rates following parathyroidectomy for primary hyperparathyroidism are excellent, with well-documented low short-term recurrence rates of hypercalcaemia. Rates of long-term recurrence have been investigated to a lesser extent, but recent studies have reported higher than anticipated rates. This study sought to evaluate recurrence rates at more than four years post seemingly corrective surgery and depending on the findings, propose whether recommendations of annual calcium monitoring post-parathyroidectomy are appropriate based on the limited data available at the time of formulating guidelines. METHODS: Fifty-two sequential parathyroidectomies for primary hyperparathyroidism from 2014-2016 from a single unit were retrospectively followed up with serum calcium levels. A hospital computer system was used to collect data on pre-operative, immediate post-operative and most recent follow-up calcium levels. Patients were excluded if there was no minimum of 48 months between the operation date and most recent calcium. Recurrence was defined as hypercalcaemia more than six months after eucalcaemia post-parathyroidectomy. RESULTS: Of the 52 cases analysed, two were lost to long-term follow-up, two patients died during the follow-up period while 10 did not meet the inclusion criteria of at least 48 months follow-up. This resulted in a cohort of 38 patients (mean age 66.4 years, 78.9% female). The median follow-up of 73.17 months (range 48.77-95.47 months) demonstrated a hypercalcaemia recurrence of 5.26% (2/38 patients). These cases were due to misdiagnosed parathyroid hyperplasia as opposed to suspected adenoma. Therefore, the long-term cure rate was 94.74% (36/38 patients). CONCLUSION: These findings support the high cure rates and low recurrence rates of the numerous short-term studies already performed despite a longer follow-up period. This is in contrast to recent series which have documented a higher recurrence in the long-term. This study would, therefore, suggests recommendations of annual calcium monitoring are excessive and that less frequent calcium monitoring is necessary in the first few years post-operation. However, the 5.26% recurrence rate in this study is not insignificant and follow-up is still paramount. Therefore, following the initial post-operative assessment, the authors propose a follow-up at the five-year mark and an annual continuation from this point forward due to the evidenced delayed recurrence of hypercalcaemia.
ABSTRACT
Source localization with a geoacoustic model requires optimizing the model over a parameter space of range and depth with the objective of matching a predicted sound field to a field measured on an array. We propose a sample-efficient sequential Bayesian optimization strategy that models the objective function as a Gaussian process (GP) surrogate model conditioned on observed data. Using the mean and covariance functions of the GP, a heuristic acquisition function proposes a candidate in parameter space to sample, balancing exploitation (sampling around the best observed objective function value) and exploration (sampling in regions of high variance in the GP). The candidate sample is evaluated, and the GP conditioned on the updated data. Optimization proceeds sequentially until a fixed budget of evaluations is expended. We demonstrate source localization for a shallow-water waveguide using Monte Carlo simulations and experimental data from an acoustic source tow. Compared to grid search and quasi-random sampling strategies, simulations and experimental results indicate the Bayesian optimization strategy converges on optimal solutions rapidly.
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Aims: In this study, we aim to determine whether combining multiple small colorectal polyps within a single specimen pot can reduce carbon footprint, without an associated deleterious clinical impact. Methods: This was a retrospective observational study of colorectal polyps resected during 2019, within the Imperial College Healthcare Trust. The numbers of pots for polypectomy specimens were calculated and corresponding histology results were extracted. We modelled the potential reduction in carbon footprint if all less than 10 mm polyps were sent together and the number of advanced lesions we would not be able to locate if we adopted this strategy. Carbon footprint was estimated based on previous study using a life-cycle assessment, at 0.28 kgCO2e per pot. Results: A total of 11 781 lower gastrointestinal endoscopies were performed. There were 5125 polyps removed and 4192 pots used, equating to a carbon footprint of 1174 kgCO2e. There were 4563 (89%) polyps measuring 0-10 mm. 6 (0.1%) of these polyps were cancers, while 12 (0.2%) demonstrated high-grade dysplasia. If we combined all small polyps in a single pot, total pot usage could be reduced by one-third (n=2779). Conclusion: A change in practice by placing small polyps collectively in one pot would have resulted in reduction in carbon footprint equivalent to 396 kgCO2e (emissions from 982 miles driven by an average passenger car). The reduction in carbon footprint from judicious use of specimen pots would be amplified with a change in practice on a national level.
ABSTRACT
Pituitary apoplexy is an endocrine-related emergency most commonly caused by hemorrhage into a preexisting pituitary adenoma. Known risk factors for such hemorrhage include major surgical procedures, head trauma, pregnancy, anticoagulation, and the administration of hormone therapies for the correction of primary hypothalamic deficiencies. Elective orthopedic surgery is an uncommon precipitator of pituitary apoplexy that is rarely described. We report the case of a patient with a previously unknown pituitary macroadenoma who developed apoplexy as a complication of elective right total hip arthroplasty.
ABSTRACT
Gas exchange between the atmosphere and ocean interior profoundly impacts global climate and biogeochemistry. However, our understanding of the relevant physical processes remains limited by a scarcity of direct observations. Dissolved noble gases in the deep ocean are powerful tracers of physical air-sea interaction due to their chemical and biological inertness, yet their isotope ratios have remained underexplored. Here, we present high-precision noble gas isotope and elemental ratios from the deep North Atlantic (~32°N, 64°W) to evaluate gas exchange parameterizations using an ocean circulation model. The unprecedented precision of these data reveal deep-ocean undersaturation of heavy noble gases and isotopes resulting from cooling-driven air-to-sea gas transport associated with deep convection in the northern high latitudes. Our data also imply an underappreciated and large role for bubble-mediated gas exchange in the global air-sea transfer of sparingly soluble gases, including O2, N2, and SF6. Using noble gases to validate the physical representation of air-sea gas exchange in a model also provides a unique opportunity to distinguish physical from biogeochemical signals. As a case study, we compare dissolved N2/Ar measurements in the deep North Atlantic to physics-only model predictions, revealing excess N2 from benthic denitrification in older deep waters (below 2.9 km). These data indicate that the rate of fixed N removal in the deep Northeastern Atlantic is at least three times higher than the global deep-ocean mean, suggesting tight coupling with organic carbon export and raising potential future implications for the marine N cycle.
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BACKGROUND: Type 2 myocardial infarction is caused by myocardial oxygen supply-demand imbalance, and its diagnosis is increasingly common with the advent of high-sensitivity cardiac troponin assays. Although this diagnosis is associated with poor outcomes, widespread uncertainty and confusion remain among clinicians as to how to investigate and manage this heterogeneous group of patients with type 2 myocardial infarction. METHODS: In a prospective cohort study, 8064 consecutive patients with increased cardiac troponin concentrations were screened to identify patients with type 2 myocardial infarction. We excluded patients with frailty or renal or hepatic failure. All study participants underwent coronary (invasive or computed tomography angiography) and cardiac (magnetic resonance or echocardiography) imaging, and the underlying causes of infarction were independently adjudicated. The primary outcome was the prevalence of coronary artery disease. RESULTS: In 100 patients with a provisional diagnosis of type 2 myocardial infarction (median age, 65 years [interquartile range, 55-74 years]; 43% women), coronary and cardiac imaging reclassified the diagnosis in 7 patients: type 1 or 4b myocardial infarction in 5 and acute myocardial injury in 2 patients. In those with type 2 myocardial infarction, median cardiac troponin I concentrations were 195 ng/L (interquartile range, 62-760 ng/L) at presentation and 1165 ng/L (interquartile range, 277-3782 ng/L) on repeat testing. The prevalence of coronary artery disease was 68% (63 of 93), which was obstructive in 30% (28 of 93). Infarct-pattern late gadolinium enhancement or regional wall motion abnormalities were observed in 42% (39 of 93), and left ventricular systolic dysfunction was seen in 34% (32 of 93). Only 10 patients had both normal coronary and normal cardiac imaging. Coronary artery disease and left ventricular systolic dysfunction were previously unrecognized in 60% (38 of 63) and 84% (27 of 32), respectively, with only 33% (21 of 63) and 19% (6 of 32) on evidence-based treatments. CONCLUSIONS: Systematic coronary and cardiac imaging of patients with type 2 myocardial infarction identified coronary artery disease in two-thirds and left ventricular systolic dysfunction in one-third of patients. Unrecognized and untreated coronary or cardiac disease is seen in most patients with type 2 myocardial infarction, presenting opportunities for initiation of evidence-based treatments with major potential to improve clinical outcomes. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03338504.
Subject(s)
Anterior Wall Myocardial Infarction , Coronary Artery Disease , Myocardial Infarction , Ventricular Dysfunction, Left , Aged , Contrast Media , Coronary Artery Disease/diagnostic imaging , Coronary Artery Disease/epidemiology , Female , Gadolinium , Humans , Male , Myocardial Infarction/complications , Myocardial Infarction/diagnosis , Myocardial Infarction/epidemiology , Prospective Studies , Troponin I , Ventricular Dysfunction, Left/complicationsABSTRACT
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. 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. 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 [95% CI: 3.1-34.8]; 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 [95% CI: 1.9-12.2]; 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 [95% CI: 2.33-28.7], 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).
Subject(s)
Aortic Valve Stenosis , Atherosclerosis , Cardiovascular Diseases , Myocardial Infarction , Plaque, Atherosclerotic , Stroke , Calcium , Fluorine Radioisotopes , Humans , Myocardial Infarction/complications , Myocardial Infarction/diagnostic imaging , Positron Emission Tomography Computed Tomography/methods , Predictive Value of Tests , Radiopharmaceuticals , Sodium Fluoride , Stroke/diagnostic imaging , Stroke/etiologyABSTRACT
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 18F-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 18F-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.
Subject(s)
Alendronate/therapeutic use , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/drug therapy , Bone Density Conservation Agents/therapeutic use , Denosumab/therapeutic use , Disease Progression , Aged , Aged, 80 and over , Aortic Valve Stenosis/metabolism , Double-Blind Method , Female , Humans , Male , Middle Aged , Positron Emission Tomography Computed Tomography , Treatment Outcome , Vascular Calcification/diagnostic imaging , Vascular Calcification/drug therapy , Vascular Calcification/metabolismABSTRACT
OBJECTIVE: CT 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. METHODS: Subjects 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. RESULTS: A 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). CONCLUSION: CT-AVC is reproducible and demonstrates larger increases over time normalised to measurement repeatability compared with echocardiographic measures.
Subject(s)
Aortic Valve Stenosis/diagnosis , Aortic Valve/diagnostic imaging , Calcium/metabolism , Multidetector Computed Tomography/methods , Aged , Aortic Valve/metabolism , Aortic Valve Stenosis/metabolism , Echocardiography, Doppler , Female , Follow-Up Studies , Humans , Male , Middle Aged , Reproducibility of Results , Retrospective Studies , Severity of Illness IndexSubject(s)
Aortic Valve Stenosis , Calcinosis , Aortic Valve , Female , Humans , Male , Predictive Value of Tests , Sex CharacteristicsABSTRACT
OBJECTIVE: First-phase ejection fraction (EF1) is a novel measure of early left ventricular systolic dysfunction. We investigated determinants of EF1 and its prognostic value in aortic stenosis. METHODS: EF1 was measured retrospectively in participants of an echocardiography/cardiovascular magnetic resonance cohort study which recruited patients with aortic stenosis (peak aortic velocity of ≥2 m/s) between 2012 and 2014. Linear regression models were constructed to examine variables associated with EF1. Cox proportional hazards were used to determine the prognostic power of EF1 for aortic valve replacement (AVR, performed as part of clinical care in accordance with international guidelines) or death. RESULTS: Total follow-up of the 149 participants (69.8% male, 70 (65-76) years, mean gradient 33 (21-42) mm Hg) was 238 029 person-days. Sixty-seven participants (45%) had a low baseline EF1 (<25%) despite normal ejection fraction (67% (62%-71%)). Patients with low EF1 had more severe aortic stenosis (mean gradient 39 (34-45) mm Hg vs 24 (16-35) mm Hg, p<0.001) and more myocardial fibrosis (indexed extracellular volume (iECV) (24.2 (19.6-28.7) mL/m2 vs 20.6 (16.8-24.3) mL/m2, p=0.002; late gadolinium enhancement (LGE) prevalence 52% vs 20%, p<0.001). Zva, iECV and infarct LGE were independent predictors of EF1. EF1 improved post-AVR (n=57 with post-AVR EF1 available, baseline 16 (12-24) vs follow-up 27% (22%-31%); p<0.001). Low baseline EF1 was an independent predictor of AVR/death (HR 5.6, 95% CI 3.4 to 9.4), driven by AVR. CONCLUSION: EF1 quantifies early, potentially reversible systolic dysfunction in aortic stenosis, is associated with global afterload and myocardial fibrosis, and is an independent predictor of AVR.
Subject(s)
Aortic Valve Stenosis/diagnostic imaging , Aortic Valve/diagnostic imaging , Echocardiography , Hemodynamics , Stroke Volume , Ventricular Function, Left , Aged , Aortic Valve/pathology , Aortic Valve/physiopathology , Aortic Valve Stenosis/pathology , Aortic Valve Stenosis/physiopathology , Female , Fibrosis , Humans , Magnetic Resonance Imaging, Cine , Male , Middle Aged , Myocardium/pathology , Predictive Value of Tests , Prognosis , Retrospective StudiesABSTRACT
OBJECTIVES: Intraplaque angiogenesis and inflammation are key promoters of atherosclerosis and are mediated by the alpha-V beta-3 (αvß3) integrin pathway. We investigated the applicability of the αvß3-integrin receptor-selective positron emission tomography (PET) radiotracer 18F-fluciclatide in assessing human aortic atherosclerosis. METHODS: Vascular 18F-fluciclatide binding was evaluated using ex vivo analysis of carotid endarterectomy samples with autoradiography and immunohistochemistry, and in vivo kinetic modelling following radiotracer administration. Forty-six subjects with a spectrum of atherosclerotic disease categorised as stable (n=27) or unstable (n=19; recent myocardial infarction) underwent PET and CT imaging of the thorax after administration of 229 (IQR 217-237) MBq 18F-fluciclatide. Thoracic aortic 18F-fluciclatide uptake was quantified on fused PET-CT images and corrected for blood-pool activity using the maximum tissue-to-background ratio (TBRmax). Aortic atherosclerotic burden was quantified by CT wall thickness, plaque volume and calcium scoring. RESULTS: 18F-Fluciclatide uptake co-localised with regions of increased αvß3 integrin expression, and markers of inflammation and angiogenesis. 18F-Fluciclatide vascular uptake was confirmed in vivo using kinetic modelling, and on static imaging correlated with measures of aortic atherosclerotic burden: wall thickness (r=0.57, p=0.001), total plaque volume (r=0.56, p=0.001) and aortic CT calcium score (r=0.37, p=0.01). Patients with recent myocardial infarction had greater aortic 18F-fluciclatide uptake than those with stable disease (TBRmax 1.29 vs 1.21, p=0.02). CONCLUSIONS: In vivo expression of αvß3 integrin in human aortic atheroma is associated with plaque burden and is increased in patients with recent myocardial infarction. Quantification of αvß3 integrin expression with 18F-fluciclatide PET has potential to assess plaque vulnerability and disease activity in atherosclerosis.
Subject(s)
Aortic Diseases/diagnostic imaging , Aortic Diseases/metabolism , Atherosclerosis/diagnostic imaging , Atherosclerosis/metabolism , Integrin alphaVbeta3/metabolism , Aged , Aorta, Thoracic/diagnostic imaging , Aorta, Thoracic/metabolism , Carboxylic Acids/pharmacokinetics , Carotid Stenosis/diagnostic imaging , Carotid Stenosis/metabolism , Cyclobutanes/pharmacokinetics , Female , Humans , Image Interpretation, Computer-Assisted/methods , Male , Middle Aged , Myocardial Infarction/diagnostic imaging , Myocardial Infarction/metabolism , Positron Emission Tomography Computed Tomography/methods , Radiopharmaceuticals/pharmacokinetics , Vascular Calcification/diagnostic imaging , Vascular Calcification/metabolismABSTRACT
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.
Subject(s)
Aortic Valve Stenosis/blood , Apolipoprotein B-100/blood , Calcinosis/complications , Disease Progression , Lipoprotein(a)/blood , Phospholipids/blood , Age Factors , Aged , Aged, 80 and over , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/etiology , Biomarkers/blood , Calcinosis/blood , Cohort Studies , Echocardiography, Doppler/methods , Female , Humans , Hyperlipidemias/blood , Hyperlipidemias/complications , Hyperlipidemias/mortality , Male , Middle Aged , Positron-Emission Tomography/methods , Prognosis , Proportional Hazards Models , Prospective Studies , Risk Assessment , Sex Factors , Survival Analysis , Tomography, X-Ray Computed/methodsABSTRACT
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 multimodality approach including positron emission tomography, computed tomography, 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 (inflammation activity) positron emission tomography, computed tomography calcium scoring, and echocardiography. Sixty patients underwent repeat computed tomography 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, 2.32 [95% CI, 1.81-3.27] versus 1.30 [1.22-1.49]; P<0.001) and 18F-Fluorodeoxyglucose activity (tissue-to-background ratio, 1.44 [1.37-1.58] versus 1.17 [1.12-1.24]; P<0.001) compared with patients without MAC. MAC activity (18F-fluoride uptake) was closely associated with the local calcium score and 18F-Fluorodeoxyglucose uptake, as well as female sex and renal function. Similarly, MAC progression was closely associated with local factors, in particular, baseline MAC. Traditional cardiovascular risk factors and calcification activity in bone or remote atherosclerotic areas were not associated with disease activity nor progression. CONCLUSIONS: MAC is characterized by increased local calcification activity and inflammation. Baseline MAC burden was associated with disease activity and the rate of subsequent progression. This suggests a self-perpetuating cycle of calcification and inflammation that may be the target of future therapeutic interventions.
Subject(s)
Calcinosis/diagnostic imaging , Heart Valve Diseases/diagnostic imaging , Mitral Valve/diagnostic imaging , Multimodal Imaging/methods , Aged , Aged, 80 and over , Aortic Valve/diagnostic imaging , Aortic Valve/pathology , Aortic Valve/physiopathology , Aortic Valve Stenosis/diagnostic imaging , Aortic Valve Stenosis/epidemiology , Aortic Valve Stenosis/physiopathology , Calcinosis/epidemiology , Calcinosis/physiopathology , Computed Tomography Angiography , Coronary Angiography/methods , Disease Progression , Echocardiography , Female , Heart Valve Diseases/epidemiology , Heart Valve Diseases/physiopathology , Humans , Incidence , Male , Middle Aged , Mitral Valve/physiopathology , Positron Emission Tomography Computed Tomography , Predictive Value of Tests , Prevalence , Prognosis , Time FactorsABSTRACT
Natural mechanisms in the ocean, both physical and biological, concentrate carbon in the deep ocean, resulting in lower atmospheric carbon dioxide. The signals of these carbon pumps overlap to create the observed carbon distribution in the ocean, making the individual impact of each pump difficult to disentangle. Noble gases have the potential to directly quantify the physical carbon solubility pump and to indirectly improve estimates of the biological organic carbon pump. Noble gases are biologically inert, can be precisely measured, and span a range of physical properties. We present dissolved neon, argon, and krypton data spanning the Atlantic, Southern, Pacific, and Arctic Oceans. Comparisons between deep-ocean observations and models of varying complexity enable the rates of processes that control the carbon solubility pump to be quantified and thus provide an important metric for ocean model skill. Noble gases also provide a powerful means of assessing air-sea gas exchange parameterizations.
Subject(s)
Carbon Dioxide/metabolism , Noble Gases/chemistry , Seawater/chemistry , Arctic Regions , Carbon Dioxide/analysis , Oceans and SeasABSTRACT
Tectonic landforms reveal that the West Antarctic Ice Sheet (WAIS) lies atop a major volcanic rift system. However, identifying subglacial volcanism is challenging. Here we show geochemical evidence of a volcanic heat source upstream of the fast-melting Pine Island Ice Shelf, documented by seawater helium isotope ratios at the front of the Ice Shelf cavity. The localization of mantle helium to glacial meltwater reveals that volcanic heat induces melt beneath the grounded glacier and feeds the subglacial hydrological network crossing the grounding line. The observed transport of mantle helium out of the Ice Shelf cavity indicates that volcanic heat is supplied to the grounded glacier at a rate of ~ 2500 ± 1700 MW, which is ca. half as large as the active Grimsvötn volcano on Iceland. Our finding of a substantial volcanic heat source beneath a major WAIS glacier highlights the need to understand subglacial volcanism, its hydrologic interaction with the marine margins, and its potential role in the future stability of the WAIS.
ABSTRACT
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<0.001) after adjustment for age, sex, peak velocity, and aortic valve area. Among 210 (23%) patients with discordant echocardiographic assessments, there was considerable heterogeneity in CT-AVC scores, which again were an independent predictor of clinical outcomes (hazard ratio, 3.67 [95% confidence interval, 1.39-9.73]; 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.