Effect of Denosumab or Alendronic Acid on the Progression of Aortic Stenosis: A Double-Blind Randomized Controlled Trial.

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.

First-phase ejection fraction by cardiovascular magnetic resonance predicts outcomes in aortic stenosis.

BACKGROUND: First-phase ejection fraction (EF1; the ejection fraction measured during active systole up to the time of maximal aortic flow) measured by transthoracic echocardiography (TTE) is a powerful predictor of outcomes in patients with aortic stenosis. We aimed to assess whether cardiovascular magnetic resonance (CMR) might provide more precise measurements of EF1 than TTE and to examine the correlation of CMR EF1 with measures of fibrosis. METHODS: In 141 patients with at least mild aortic stenosis, we measured CMR EF1 from a short-axis 3D stack and compared its variability with TTE EF1, and its associations with myocardial fibrosis and clinical outcome (aortic valve replacement (AVR) or death). RESULTS: Intra- and inter-observer variation of CMR EF1 (standard deviations of differences within and between observers of 2.3% and 2.5% units respectively) was approximately 50% that of TTE EF1. CMR EF1 was strongly predictive of AVR or death. On multivariable Cox proportional hazards analysis, the hazard ratio for CMR EF1 was 0.93 (95% confidence interval 0.89-0.97, p = 0.001) per % change in EF1 and, apart from aortic valve gradient, CMR EF1 was the only imaging or biochemical measure independently predictive of outcome. Indexed extracellular volume was associated with AVR or death, but not after adjusting for EF1. CONCLUSIONS: EF1 is a simple robust marker of early left ventricular impairment that can be precisely measured by CMR and predicts outcome in aortic stenosis. Its measurement by CMR is more reproducible than that by TTE and may facilitate left ventricular structure-function analysis.

Left ventricular hypertrophy with strain and aortic stenosis.

BACKGROUND: ECG left ventricular hypertrophy with strain is associated with an adverse prognosis in aortic stenosis. We investigated the mechanisms and outcomes associated with ECG strain. METHODS AND RESULTS: One hundred and two patients (age, 70 years [range, 63-75 years]; male, 66%; aortic valve area, 0.9 cm(2) [range, 0.7-1.2 cm(2)]) underwent ECG, echocardiography, and cardiovascular magnetic resonance. They made up the mechanism cohort. Myocardial fibrosis was determined with late gadolinium enhancement (replacement fibrosis) and T1 mapping (diffuse fibrosis). The relationship between ECG strain and cardiovascular magnetic resonance was then assessed in an external validation cohort (n=64). The outcome cohort was made up of 140 patients from the Scottish Aortic Stenosis and Lipid Lowering Trial Impact on Regression (SALTIRE) study and was followed up for 10.6 years (1254 patient-years). Compared with those without left ventricular hypertrophy (n=51) and left ventricular hypertrophy without ECG strain (n=30), patients with ECG strain (n=21) had more severe aortic stenosis, increased left ventricular mass index, more myocardial injury (high-sensitivity plasma cardiac troponin I concentration, 4.3 ng/L [interquartile range, 2.5-7.3 ng/L] versus 7.3 ng/L [interquartile range, 3.2-20.8 ng/L] versus 18.6 ng/L [interquartile range, 9.0-45.2 ng/L], respectively; P<0.001) and increased diffuse fibrosis (extracellular volume fraction, 27.4±2.2% versus 27.2±2.9% versus 30.9±1.9%, respectively; P<0.001). All patients with ECG strain had midwall late gadolinium enhancement (positive and negative predictive values of 100% and 86%, respectively). Indeed, late gadolinium enhancement was independently associated with ECG strain (odds ratio, 1.73; 95% confidence interval, 1.08-2.77; P=0.02), a finding confirmed in the validation cohort. In the outcome cohort, ECG strain was an independent predictor of aortic valve replacement or cardiovascular death (hazard ratio, 2.67; 95% confidence interval, 1.35-5.27; P<0.01). CONCLUSION: ECG strain is a specific marker of midwall myocardial fibrosis and predicts adverse clinical outcomes in aortic stenosis.

A genome-wide scan identifies mutations in the gene encoding phosphodiesterase 11A4 (PDE11A) in individuals with adrenocortical hyperplasia.

Phosphodiesterases (PDEs) regulate cyclic nucleotide levels. Increased cyclic AMP (cAMP) signaling has been associated with PRKAR1A or GNAS mutations and leads to adrenocortical tumors and Cushing syndrome. We investigated the genetic source of Cushing syndrome in individuals with adrenocortical hyperplasia that was not caused by known defects. We performed genome-wide SNP genotyping, including the adrenocortical tumor DNA. The region with the highest probability to harbor a susceptibility gene by loss of heterozygosity (LOH) and other analyses was 2q31-2q35. We identified mutations disrupting the expression of the PDE11A isoform-4 gene (PDE11A) in three kindreds. Tumor tissues showed 2q31-2q35 LOH, decreased protein expression and high cyclic nucleotide levels and cAMP-responsive element binding protein (CREB) phosphorylation. PDE11A codes for a dual-specificity PDE that is expressed in adrenal cortex and is partially inhibited by tadalafil and other PDE inhibitors; its germline inactivation is associated with adrenocortical hyperplasia, suggesting another means by which dysregulation of cAMP signaling causes endocrine tumors.

Systematic hand-held echocardiography in patients hospitalised with acute coronary syndrome.

AIMS: Transthoracic echocardiography is recommended in all patients with acute coronary syndrome but is time-consuming and lacks an evidence base. We aimed to assess the feasibility, diagnostic accuracy and time-efficiency of hand-held echocardiography in patients with acute coronary syndrome and describe the impact of echocardiography on clinical management in this setting. METHODS AND RESULTS: Patients with acute coronary syndrome underwent both hand-held and transthoracic echocardiography with agreement between key imaging parameters assessed using kappa statistics. The immediate clinical impact of hand-held echocardiography in this population was systematically evaluated.Overall, 262 patients (65±12 years, 71% male) participated. Agreement between hand-held and transthoracic echocardiography was good-to-excellent (kappa 0.60-1.00) with hand-held echocardiography having an overall negative predictive value of 95%. Hand-held echocardiography was performed rapidly (7.7±1.6 min) and completed a median of 5 [interquartile range 3-20] hours earlier than transthoracic echocardiography. Systematic hand-held echocardiography in all patients with acute coronary syndrome identified an important cardiac abnormality in 50% and the clinical management plan was changed by echocardiography in 42%. In 85% of cases, hand-held echocardiography was sufficient for patient decision-making and transthoracic echocardiography was no longer deemed necessary. CONCLUSIONS: In patients with acute coronary syndrome, hand-held echocardiography provides comparable results to transthoracic echocardiography, can be more rapidly applied and gives sufficient imaging information for decision-making in the vast majority of patients. Systematic echocardiography has clinical impact in half of patients, supporting the clinical utility of echocardiography in this population, and providing an evidence-base for current guidelines.

Assessment of valvular calcification and inflammation by positron emission tomography in patients with aortic stenosis.

BACKGROUND: The pathophysiology of aortic stenosis is incompletely understood, and the relative contributions of valvular calcification and inflammation to disease progression are unknown. METHODS AND RESULTS: Patients with aortic sclerosis and mild, moderate, and severe stenosis were compared prospectively with age- and sex-matched control subjects. Aortic valve severity was determined by echocardiography. Calcification and inflammation in the aortic valve were assessed by 18F-sodium fluoride (18F-NaF) and 18F-fluorodeoxyglucose (18F-FDG) uptake with the use of positron emission tomography. One hundred twenty-one subjects (20 controls; 20 aortic sclerosis; 25 mild, 33 moderate, and 23 severe aortic stenosis) were administered both 18F-NaF and 18F-FDG. Quantification of tracer uptake within the valve demonstrated excellent interobserver repeatability with no fixed or proportional biases and limits of agreement of ±0.21 (18F-NaF) and ±0.13 (18F-FDG) for maximum tissue-to-background ratios. Activity of both tracers was higher in patients with aortic stenosis than in control subjects (18F-NaF: 2.87±0.82 versus 1.55±0.17; 18F-FDG: 1.58±0.21 versus 1.30±0.13; both P<0.001). 18F-NaF uptake displayed a progressive rise with valve severity (r(2)=0.540, P<0.001), with a more modest increase observed for 18F-FDG (r(2)=0.218, P<0.001). Among patients with aortic stenosis, 91% had increased 18F-NaF uptake (>1.97), and 35% had increased 18F-FDG uptake (>1.63). A weak correlation between the activities of these tracers was observed (r(2)=0.174, P<0.001). CONCLUSIONS: Positron emission tomography is a novel, feasible, and repeatable approach to the evaluation of valvular calcification and inflammation in patients with aortic stenosis. The frequency and magnitude of increased tracer activity correlate with disease severity and are strongest for 18F-NaF. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT01358513.

Cytomegalovirus survival on common environmental surfaces: opportunities for viral transmission.

Congenital cytomegalovirus (CMV) affects ~1 of 150 births and is a leading cause of hearing loss and intellectual disability. It has been suggested that transmission may occur via contaminated surfaces. CMV AD169 in filtered human saliva, applied to environmental surfaces, was recovered at various time points. Samples were evaluated by culture and real-time polymerase chain reaction. CMV was found viable on metal and wood to 1 hour, glass and plastic to 3 hours, and rubber, cloth, and cracker to 6 hours. CMV was cultured from 83 of 90 wet and 5 of 40 dry surfaces. CMV was more likely to be isolated from wet, highly absorbent surfaces at earlier time points.

Serum lipoprotein(a) and bioprosthetic aortic valve degeneration.

AIMS: Bioprosthetic aortic valve degeneration demonstrates pathological similarities to aortic stenosis. Lipoprotein(a) [Lp(a)] is a well-recognized risk factor for incident aortic stenosis and disease progression. The aim of this study is to investigate whether serum Lp(a) concentrations are associated with bioprosthetic aortic valve degeneration. METHODS AND RESULTS: In a post hoc analysis of a prospective multimodality imaging study (NCT02304276), serum Lp(a) concentrations, echocardiography, contrast-enhanced computed tomography (CT) angiography, and 18F-sodium fluoride (18F-NaF) positron emission tomography (PET) were assessed in patients with bioprosthetic aortic valves. Patients were also followed up for 2 years with serial echocardiography. Serum Lp(a) concentrations [median 19.9 (8.4-76.4) mg/dL] were available in 97 participants (mean age 75 ± 7 years, 54% men). There were no baseline differences across the tertiles of serum Lp(a) concentrations for disease severity assessed by echocardiography [median peak aortic valve velocity: highest tertile 2.5 (2.3-2.9) m/s vs. lower tertiles 2.7 (2.4-3.0) m/s, P = 0.204], or valve degeneration on CT angiography (highest tertile n = 8 vs. lower tertiles n = 12, P = 0.552) and 18F-NaF PET (median tissue-to-background ratio: highest tertile 1.13 (1.05-1.41) vs. lower tertiles 1.17 (1.06-1.53), P = 0.889]. After 2 years of follow-up, there were no differences in annualized change in bioprosthetic hemodynamic progression [change in peak aortic valve velocity: highest tertile [0.0 (-0.1-0.2) m/s/year vs. lower tertiles 0.1 (0.0-0.2) m/s/year, P = 0.528] or the development of structural valve degeneration. CONCLUSION: Serum lipoprotein(a) concentrations do not appear to be a major determinant or mediator of bioprosthetic aortic valve degeneration.

Influence of Literacy, Self-Efficacy, and Social Support on Diabetes-Related Outcomes Following Hospital Discharge.

Objective: To evaluate the relationship between health literacy, social support, and self-efficacy as predictors of change in A1c and readmission among hospitalized patients with type 2 diabetes (T2D). Methods: This is a secondary analysis of patients with T2D (A1c >8.5%) enrolled in a randomized trial in which health literacy (Newest Vital Sign), social support (Multidimensional Scale of Perceived Social Support), and empowerment (Diabetes Empowerment Scale-Short Form) was assessed at baseline. Multivariable models evaluated whether these concepts were associated with A1c reduction at 12 weeks (absolute change, % with >1% reduction, % reaching individualized target) and readmission (14 and 30 days). Results: A1c (N=108) decreased >1% in 60%, while individualized A1c target was achieved in 31%. After adjustment for baseline A1c and potential confounders, health literacy was associated with significant reduction in A1c (Estimate -0.21, 95% CI -0.40, -0.01, p=0.041) and >1% decrease in A1c (OR 1.37, 95% CI 1.08, 1.73, p=0.009). However, higher social support was associated with greater adjusted odds of reaching the individualized A1c target (OR 1.63, 95% CI 1.04, 2.55, p=0.32). Both higher empowerment (OR 0.23, 95% CI 0.08, 0.64, p=0.005) and social support (OR 0.57, 95% CI 0.36, 0.91, p=0.018) were associated with fewer readmissions by 14 days, but not 30 days. Conclusion: The study indicates that health literacy and social support may be important predictors of A1c reduction post-discharge among hospitalized patients with T2D. Social support and diabetes self-management skills should be addressed and early follow-up may be critical for avoiding readmissions. Clinical Trial: NCT03455985.

Effectiveness of a Diabetes-Focused Electronic Discharge Order Set and Postdischarge Nursing Support Among Poorly Controlled Hospitalized Patients: Randomized Controlled Trial.

BACKGROUND: Although the use of electronic order sets has become standard practice for inpatient diabetes management, there is limited decision support at discharge. OBJECTIVE: In this study, we assessed whether an electronic discharge order set (DOS) plus nurse follow-up calls improve discharge orders and postdischarge outcomes among hospitalized patients with type 2 diabetes mellitus. METHODS: This was a randomized, open-label, single center study that compared an electronic DOS and nurse phone calls to enhanced standard care (ESC) in hospitalized insulin-requiring patients with type 2 diabetes mellitus. The primary outcome was change in glycated hemoglobin (HbA1c) level at 24 weeks after discharge. The secondary outcomes included the completeness and accuracy of discharge prescriptions related to diabetes. RESULTS: This study was stopped early because of feasibility concerns related to the long-term follow-up. However, 158 participants were enrolled (DOS: n=82; ESC: n=76), of whom 155 had discharge data. The DOS group had a greater frequency of prescriptions for bolus insulin (78% vs 44%; P=.01), needles or syringes (95% vs 63%; P=.03), and glucometers (86% vs 36%; P<.001). The clarity of the orders was similar. HbA1c data were available for 54 participants in each arm at 12 weeks and for 44 and 45 participants in the DOS and ESC arms, respectively, at 24 weeks. The unadjusted difference in change in HbA1c level (DOS - ESC) was -0.6% (SD 0.4%; P=.18) at 12 weeks and -1.1% (SD 0.4%; P=.01) at 24 weeks. The adjusted difference in change in HbA1c level was -0.5% (SD 0.4%; P=.20) at 12 weeks and -0.7% (SD 0.4%; P=.09) at 24 weeks. The achievement of the individualized HbA1c target was greater in the DOS group at 12 weeks but not at 24 weeks. CONCLUSIONS: An intervention that included a DOS plus a postdischarge nurse phone call resulted in more complete discharge prescriptions. The assessment of postdischarge outcomes was limited, owing to the loss of the long-term follow-up, but it suggested a possible benefit in glucose control. TRIAL REGISTRATION: ClinicalTrials.gov NCT03455985; https://clinicaltrials.gov/ct2/show/NCT03455985.

18F-GP1 Positron Emission Tomography and Bioprosthetic Aortic Valve Thrombus.

BACKGROUND: Bioprosthetic valve thrombosis may have implications for valve function and durability. OBJECTIVES: Using a novel glycoprotein IIb/IIIa receptor radiotracer 18F-GP1, we investigated whether positron emission tomography (PET)-computed tomography (CT) could detect thrombus formation on bioprosthetic aortic valves. METHODS: Ex vivo experiments were performed on human platelets and explanted bioprosthetic aortic valves. In a prospective cross-sectional study, patients with either bioprosthetic or normal native aortic valves underwent echocardiography, CT angiography, and 18F-GP1 PET-CT. RESULTS: Flow cytometric analysis, histology, immunohistochemistry, and autoradiography demonstrated selective binding of 18F-GP1 to activated platelet glycoprotein IIb/IIIa receptors and thrombus adherent to prosthetic valves. In total, 75 participants were recruited: 53 with bioprosthetic valves (median time from implantation 37 months [IQR: 12-80 months]) and 22 with normal native aortic valves. Three participants had obstructive valve thrombosis, and a further 3 participants had asymptomatic hypoattenuated leaflet thickening on CT angiography. All bioprosthetic valves, but none of the native aortic valves, demonstrated focal 18F-GP1 uptake on the valve leaflets: median maximum target-to-background ratio 2.81 (IQR: 2.29-3.48) vs 1.43 (IQR: 1.28-1.53) (P < 0.001). Higher 18F-GP1 uptake was independently associated with duration of valve implantation and hypoattenuated leaflet thickening. All 3 participants with obstructive valve thrombosis were anticoagulated for 3 months, leading to resolution of their symptoms, improvement in mean valve gradients, and a reduction in 18F-GP1 uptake. CONCLUSIONS: Adherence of activated platelets is a common and sustained finding on bioprosthetic aortic valves. 18F-GP1 uptake is higher in the presence of thrombus, regresses with anticoagulation, and has potential use as an adjunctive clinical tool. (18F-GP1 PET-CT to Detect Bioprosthetic Aortic Valve Thrombosis; NCT04073875).

Effect of hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with and without type 1 diabetes: A prospective, randomised, open-label, blinded endpoint, cross-over study.

AIMS: This study examined the effect of experimentally-induced hypoglycaemia on measures of myocardial blood flow and myocardial injury in adults with, and without, type 1 diabetes. METHODS: In a prospective, randomised, open-label, blinded, endpoint cross-over study, 17 young adults with type 1 diabetes with no cardiovascular risk factors, and 10 healthy non-diabetic volunteers, underwent hyperinsulinaemic-euglycaemic (blood glucose 4.5-5.5 mmol/L) and hypoglycaemic (2.2-2.5 mmol/L) clamps. Myocardial blood flow was assessed using transthoracic echocardiography Doppler coronary flow reserve (CFR) and myocardial injury using plasma high-sensitivity cardiac troponin I (hs-cTnI) concentration. RESULTS: During hypoglycaemia, coronary flow reserve trended non-significantly lower in those with type 1 diabetes than in the non-diabetic participants (3.54 ± 0.47 vs. 3.89 ± 0.89). A generalised linear mixed-model analysis examined diabetes status and euglycaemia or hypoglycaemia as factors affecting CFR. No statistically significant difference in CFR was observed for diabetes status (p = .23) or between euglycaemia and hypoglycaemia (p = .31). No changes in hs-cTnI occurred during hypoglycaemia or in the recovery period (p = .86). CONCLUSIONS: A small change in CFR was not statistically significant in this study, implying hypoglycaemia may require more than coronary vasomotor dysfunction to cause harm. Further larger studies are required to investigate this putative problem.

Deconstructing tissue engineered trachea: Assessing the role of synthetic scaffolds, segmental replacement and cell seeding on graft performance.

The ideal construct for tracheal replacement remains elusive in the management of long segment airway defects. Tissue engineered tracheal grafts (TETG) have been limited by the development of graft stenosis or collapse, infection, or lack of an epithelial lining. We applied a mouse model of orthotopic airway surgery to assess the impact of three critical barriers encountered in clinical applications: the scaffold, the extent of intervention, and the impact of cell seeding and characterized their impact on graft performance. First, synthetic tracheal scaffolds electrospun from polyethylene terephthalate / polyurethane (PET/PU) were orthotopically implanted in anterior tracheal defects of C57BL/6 mice. Scaffolds demonstrated complete coverage with ciliated respiratory epithelium by 2 weeks. Epithelial migration was accompanied by macrophage infiltration which persisted at long term (>6 weeks) time points. We then assessed the impact of segmental tracheal implantation using syngeneic trachea as a surrogate for the ideal tracheal replacement. Graft recovery involved local upregulation of epithelial progenitor populations and there was no evidence of graft stenosis or necrosis. Implantation of electrospun synthetic tracheal scaffold for segmental replacement resulted in respiratory distress and required euthanasia at an early time point. There was limited epithelial coverage of the scaffold with and without seeded bone marrow-derived mononuclear cells (BM-MNCs). We conclude that synthetic scaffolds support re-epithelialization in orthotopic patch implantation, syngeneic graft integration occurs with focal repair mechanisms, however epithelialization in segmental synthetic scaffolds is limited and is not influenced by cell seeding. STATEMENT OF SIGNIFICANCE: The life-threatening nature of long-segment tracheal defects has led to clinical use of tissue engineered tracheal grafts in the last decade for cases of compassionate use. However, the ideal tracheal reconstruction using tissue-engineered tracheal grafts (TETG) has not been clarified. We addressed the core challenges in tissue engineered tracheal replacement (re-epithelialization and graft patency) by defining the role of cell seeding with autologous bone marrow-derived mononuclear cells, the mechanism of respiratory epithelialization and proliferation, and the role of the inflammatory immune response in regeneration. This research will facilitate comprehensive understanding of cellular regeneration and neotissue formation on TETG, which will permit targeted therapies for accelerating re-epithelialization and attenuating stenosis in tissue engineered airway replacement.

Computed tomography aortic valve calcium scoring for the assessment of aortic stenosis progression.

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.

Determinants and prognostic value of echocardiographic first-phase ejection fraction in aortic stenosis.

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.

Global evaluation of echocardiography in patients with COVID-19.

AIMS: To describe the cardiac abnormalities in patients with COVID-19 and identify the characteristics of patients who would benefit most from echocardiography. METHODS AND RESULTS: In a prospective international survey, we captured echocardiography findings in patients with presumed or confirmed COVID-19 between 3 and 20 April 2020. Patient characteristics, indications, findings, and impact of echocardiography on management were recorded. Multivariable logistic regression identified predictors of echocardiographic abnormalities. A total of 1216 patients [62 (52-71) years, 70% male] from 69 countries across six continents were included. Overall, 667 (55%) patients had an abnormal echocardiogram. Left and right ventricular abnormalities were reported in 479 (39%) and 397 (33%) patients, respectively, with evidence of new myocardial infarction in 36 (3%), myocarditis in 35 (3%), and takotsubo cardiomyopathy in 19 (2%). Severe cardiac disease (severe ventricular dysfunction or tamponade) was observed in 182 (15%) patients. In those without pre-existing cardiac disease (n = 901), the echocardiogram was abnormal in 46%, and 13% had severe disease. Independent predictors of left and right ventricular abnormalities were distinct, including elevated natriuretic peptides [adjusted odds ratio (OR) 2.96, 95% confidence interval (CI) 1.75-5.05) and cardiac troponin (OR 1.69, 95% CI 1.13-2.53) for the former, and severity of COVID-19 symptoms (OR 3.19, 95% CI 1.73-6.10) for the latter. Echocardiography changed management in 33% of patients. CONCLUSION: In this global survey, cardiac abnormalities were observed in half of all COVID-19 patients undergoing echocardiography. Abnormalities were often unheralded or severe, and imaging changed management in one-third of patients.

Study protocol for resolution of organ injury in acute pancreatitis (RESORP): an observational prospective cohort study.

INTRODUCTION: Survivors of acute pancreatitis (AP) have shorter overall survival and increased incidence of new-onset cardiovascular, respiratory, liver and renal disease, diabetes mellitus and cancer compared with the general population, but the mechanisms that explain this are yet to be elucidated. Our aim is to characterise the precise nature and extent of organ dysfunction following an episode of AP. METHODS AND ANALYSIS: This is an observational prospective cohort study in a single centre comprising a University hospital with an acute and emergency receiving unit and clinical research facility. Participants will be adult patient admitted with AP. Participants will undergo assessment at recruitment, 3 months and 3 years. At each time point, multiple biochemical and/or physiological assessments to measure cardiovascular, respiratory, liver, renal and cognitive function, diabetes mellitus and quality of life. Recruitment was from 30 November 2017 to 31 May 2020; last follow-up measurements is due on 31 May 2023. The primary outcome measure is the incidence of new-onset type 3c diabetes mellitus during follow-up. Secondary outcome measures include: quality of life analyses (SF-36, Gastrointestinal Quality of Life Index); montreal cognitive assessment; organ system physiological performance; multiomics predictors of AP severity, detection of premature cellular senescence. In a nested cohort within the main cohort, individuals may also consent to multiparameter MRI scan, echocardiography, pulmonary function testing, cardiopulmonary exercise testing and pulse-wave analysis. ETHICS AND DISSEMINATION: This study has received the following approvals: UK IRAS Number 178615; South-east Scotland Research Ethics Committee number 16/SS/0065. Results will be made available to AP survivors, caregivers, funders and other researchers. Publications will be open-access. TRIAL REGISTRATION NUMBERS: ClinicalTrials.gov Registry (NCT03342716) and ISRCTN50581876; Pre-results.

Large deletions of the PRKAR1A gene in Carney complex.

PURPOSE: Since the identification of PRKAR1A mutations in Carney complex, substitutions and small insertions/deletions have been found in approximately 70% of the patients. To date, no germ-line PRKAR1A deletion and/or insertion exceeded a few base pairs (up to 15). Although a few families map to chromosome 2, it is possible that current sequencing techniques do not detect larger gene changes in PRKAR1A -- mutation-negative individuals with Carney complex. EXPERIMENTAL DESIGN: To screen for gross alterations of the PRKAR1A gene, we applied Southern hybridization analysis on 36 unrelated Carney complex patients who did not have small intragenic mutations or large aberrations in PRKAR1A, including the probands from two kindreds mapping to chromosome 2. RESULTS: We found large PRKAR1A deletions in the germ-line of two patients with Carney complex, both sporadic cases; no changes were identified in the remaining patients, including the two chromosome-2-mapping families. In the first patient, the deletion is expected to lead to decreased PRKAR1A mRNA levels but no other effects on the protein; the molecular phenotype is predicted to be PRKAR1A haploinsufficiency, consistent with the majority of PRKAR1A mutations causing Carney complex. In the second patient, the deletion led to in-frame elimination of exon 3 and the expression of a shorter protein, lacking the primary site for interaction with the catalytic protein kinase A subunit. In vitro transfection studies of the mutant PRKAR1A showed impaired ability to bind cyclic AMP and activation of the protein kinase A enzyme. The patient bearing this mutation had a more-severe-than-average Carney complex phenotype that included the relatively rare psammomatous melanotic schwannoma. CONCLUSIONS: Large PRKAR1A deletions may be responsible for Carney complex in patients that do not have PRKAR1A gene defects identifiable by sequencing. Preliminary data indicate that these patients may have a different phenotype especially if their defect results in an expressed, abnormal version of the PRKAR1A protein.

3D angle-independent Doppler and speckle tracking for the myocardium and blood flow

A technology based on velocity ratio indices is described for application in the myocardium. Angle-independent Doppler indices, such as the pulsatility index, which employ velocity ratios, can be measured even if the ultrasound beam vector at the moving target and the motion vector are not in a known plane. The unknown plane situation is often encountered when an ultrasound beam interrogates sites in the myocardium. The velocities employed in an index calculation must be close to the same or opposite directions. The Doppler velocity ratio indices are independent of angle in 3D space as are ratio indices based on 1D strain and 1D speckle tracking. Angle-independent results with spectral Doppler methods are discussed. Possible future imaging techniques based on velocity ratios are presented. By using indices that involve ratios, several other sources of error cancel in addition to that of angular dependence for example errors due to less than optimum gain settings and beam distortion. This makes the indices reliable as research or clinical tools. Ratio techniques can be readily implemented with current commercial blood flow pulsed wave duplex Doppler equipment or with pulsed wave tissue Doppler equipment. In 70 patients where the quality of the real-time B-mode looked suitable for the Doppler velocity ratio technique, there was only one case where clear spectra could not be obtained for both the LV wall and the septum. A reproducibility study of spectra from the septum of the heart shows a 12% difference in velocity ratios in the repeat measurements.

Seeding and Implantation of a Biosynthetic Tissue-engineered Tracheal Graft in a Mouse Model.

Treatment options for congenital or secondary long segment tracheal defects have historically been limited due to an inability to replace functional tissue. Tissue engineering holds great promise as a potential solution with its ability to integrate cells and signaling molecules into a 3-dimensional scaffold. Recent work with tissue engineered tracheal grafts (TETGs) has seen some success but their translation has been limited by graft stenosis, graft collapse, and delayed epithelialization. In order to investigate the mechanisms driving these issues, we have developed a mouse model for tissue engineered tracheal graft implantation. TETGs were constructed using electrospun polymers polyethylene terephthalate (PET) and polyurethane (PU) in a mixture of PET and PU (20:80 percent weight). Scaffolds were then seeded using bone marrow mononuclear cells isolated from 6-8 week-old C57BL/6 mice by gradient centrifugation. Ten million cells per graft were seeded onto the lumen of the scaffold and allowed to incubate overnight before implantation between the third and seventh tracheal rings. These grafts were able to recapitulate the findings of stenosis and delayed epithelialization as demonstrated by histological analysis and lack of Keratin 5 and Keratin 14 basal epithelial cells on immunofluorescence. This model will serve as a tool for investigating cellular and molecular mechanisms involved in host remodeling.