Stopping anticoagulation for isolated or incidental pulmonary embolism: the STOPAPE RCT protocol.

Research question: Is withholding anticoagulation for patients with isolated or incidental subsegmental pulmonary embolism clinically and cost-effective compared with full anticoagulation for 3 months? Background: There has been an increase in the diagnosis of subsegmental pulmonary embolism since the advent of computed tomography pulmonary angiogram to investigate patients with suspected pulmonary embolism. Subsegmental pulmonary embolism is not often detectable with older nuclear medicine-based diagnostic imaging for ventilation/perfusion mismatch. The case fatality of pulmonary embolism has reduced as subsegmental pulmonary embolism diagnoses from computed tomography pulmonary angiogram have increased. There is growing equipoise about the optimal treatment for patients with subsegmental pulmonary embolism, given that full anticoagulation has significant risks of bleeding and subsegmental pulmonary embolism was not often diagnosed previously with ventilation/perfusion scanning and therefore most likely left predominantly untreated prior to the introduction of computed tomography pulmonary angiogram scanning. Objectives: Determine whether withholding anticoagulation for isolated or incidental subsegmental pulmonary embolism (i.e. subsegmental pulmonary embolism with no coexisting deep-vein thrombosis) reduces the harms of recurrent thromboembolism and major bleeding compared with 3 months of full anticoagulation at 3, 6 and 12 months. Determine the rate of complications of anticoagulation therapy (predominantly bleeding) in patients with isolated subsegmental pulmonary embolism. Determine whether not treating isolated subsegmental pulmonary embolism is acceptable to clinicians and patients. Determine the reclassification rate of subsegmental pulmonary embolism diagnoses made by general reporting radiologists when reviewed by specialist respiratory radiologists and develop a set of rules to improve general radiologists' diagnoses of subsegmental pulmonary embolism. Assess cost-effectiveness of not treating patients with isolated subsegmental pulmonary embolism with anticoagulation, taking a health service perspective. Methods: Prospective individually randomised open controlled trial with blinded end-point committee assessment for outcomes, powered for non-inferiority for recurrent venous thromboembolism and for superiority for bleeding events. An internal pilot phase is included for feasibility and acceptability of no anticoagulation. We planned to recruit 1466 patients from at least 50 acute hospital sites. Allowing for a dropout rate of 15%, this would have given us 90% power to detect a reduction in major and clinically relevant non-major bleeding from 7.3% in the anticoagulation arm to 3% in the intervention arm. We were powered to determine that a strategy of no anticoagulation was non-inferior to anticoagulation with an upper margin of a 2.3% increase in recurrent venous thromboembolism from an expected rate of 2% in those who receive full anticoagulation. We also planned to undertake a study comparing acute reporting radiologists' diagnoses of subsegmental pulmonary embolism from all computed tomography pulmonary angiograms with specialist respiratory radiologists. This would have allowed us to determine safety in the pilot study (i.e. patients with pulmonary embolism that was in fact larger than subsegmental would have been identified) and develop guidance for subsegmental pulmonary embolism diagnosis for general radiologists. Patients with lived experience of thrombosis contributed to all aspects of the trial design and were part of the Trial Management Group. Progress of study: The STOPAPE trial was stopped prematurely due to a low recruitment rate in the wake of the COVID pandemic and prioritisation of recovery of the National Institute for Health and Care Research research portfolio. There are no outcome data available for this trial. Separate NIHR Library publications will detail the linked qualitative study examining the views of patients and clinicians around withholding anticoagulation for isolated subsegmental pulmonary embolism as well as presenting all collected data of recruited patients. Funding: This article presents independent research funded by the National Institute for Health and Care Research (NIHR) Health Technology Assessment programme as award number NIHR128073. A plain language summary of this research article is available on the NIHR Journals Library Website https://doi.org/10.3310/HRCW7937.

Pulmonary embolism is a potentially serious condition, whereby blood clots cause a blockage of the blood supply to the lungs. The diagnosis of pulmonary embolism is made with a scan of the lungs, by showing areas where blood cannot get through the vessels easily due to blood clots. The treatment of pulmonary embolism includes anticoagulant medication ('blood thinners') that is taken over months and includes warfarin, an injectable form of heparin and directly acting oral anticoagulants. These medications work by preventing new clots from forming while the body's own mechanisms break down the clots. As the scanning technology for pulmonary embolism has become more sensitive, smaller clots are being diagnosed. However, small pulmonary embolisms may not cause any symptoms and may be found incidentally on scans performed for other reasons. In these situations, it is unclear whether treatment is required for the pulmonary embolism. These clots in smaller blood vessels away from the centre of the lungs (subsegmental pulmonary embolism) may be removed by the body's own mechanisms for dissolving clots without needing medications. Anticoagulant medication can cause side effects in some patients such as bleeding. For the anticoagulant medication to be appropriate in these smaller pulmonary embolisms, the benefits from preventing future blood clots (pulmonary embolism and deep-vein thrombosis) would need to outweigh the potential risks from the medication side effects. The STOPAPE study aimed to answer this question by testing whether we can safely withhold anticoagulation from patients diagnosed with subsegmental pulmonary embolism. Although we aimed to enrol 1466 patients in the trial with half getting usual care of anticoagulation and half getting no anticoagulation, we could not recruit patients quickly enough to the trial and, as a result, we could not continue with the STOPAPE study. This study protocol is published to help future research teams that wish to answer this research question.

Inflammatory risk and cardiovascular events in patients without obstructive coronary artery disease: the ORFAN multicentre, longitudinal cohort study.

BACKGROUND: Coronary computed tomography angiography (CCTA) is the first line investigation for chest pain, and it is used to guide revascularisation. However, the widespread adoption of CCTA has revealed a large group of individuals without obstructive coronary artery disease (CAD), with unclear prognosis and management. Measurement of coronary inflammation from CCTA using the perivascular fat attenuation index (FAI) Score could enable cardiovascular risk prediction and guide the management of individuals without obstructive CAD. The Oxford Risk Factors And Non-invasive imaging (ORFAN) study aimed to evaluate the risk profile and event rates among patients undergoing CCTA as part of routine clinical care in the UK National Health Service (NHS); to test the hypothesis that coronary arterial inflammation drives cardiac mortality or major adverse cardiac events (MACE) in patients with or without CAD; and to externally validate the performance of the previously trained artificial intelligence (AI)-Risk prognostic algorithm and the related AI-Risk classification system in a UK population. METHODS: This multicentre, longitudinal cohort study included 40 091 consecutive patients undergoing clinically indicated CCTA in eight UK hospitals, who were followed up for MACE (ie, myocardial infarction, new onset heart failure, or cardiac death) for a median of 2·7 years (IQR 1·4-5·3). The prognostic value of FAI Score in the presence and absence of obstructive CAD was evaluated in 3393 consecutive patients from the two hospitals with the longest follow-up (7·7 years [6·4-9·1]). An AI-enhanced cardiac risk prediction algorithm, which integrates FAI Score, coronary plaque metrics, and clinical risk factors, was then evaluated in this population. FINDINGS: In the 2·7 year median follow-up period, patients without obstructive CAD (32 533 [81·1%] of 40 091) accounted for 2857 (66·3%) of the 4307 total MACE and 1118 (63·7%) of the 1754 total cardiac deaths in the whole of Cohort A. Increased FAI Score in all the three coronary arteries had an additive impact on the risk for cardiac mortality (hazard ratio [HR] 29·8 [95% CI 13·9-63·9], p<0·001) or MACE (12·6 [8·5-18·6], p<0·001) comparing three vessels with an FAI Score in the top versus bottom quartile for each artery. FAI Score in any coronary artery predicted cardiac mortality and MACE independently from cardiovascular risk factors and the presence or extent of CAD. The AI-Risk classification was positively associated with cardiac mortality (6·75 [5·17-8·82], p<0·001, for very high risk vs low or medium risk) and MACE (4·68 [3·93-5·57], p<0·001 for very high risk vs low or medium risk). Finally, the AI-Risk model was well calibrated against true events. INTERPRETATION: The FAI Score captures inflammatory risk beyond the current clinical risk stratification and CCTA interpretation, particularly among patients without obstructive CAD. The AI-Risk integrates this information in a prognostic algorithm, which could be used as an alternative to traditional risk factor-based risk calculators. FUNDING: British Heart Foundation, NHS-AI award, Innovate UK, National Institute for Health and Care Research, and the Oxford Biomedical Research Centre.

Uncertainty quantification in computed tomography pulmonary angiography.

Computed tomography (CT) imaging of the thorax is widely used for the detection and monitoring of pulmonary embolism (PE). However, CT images can contain artifacts due to the acquisition or the processes involved in image reconstruction. Radiologists often have to distinguish between such artifacts and actual PEs. We provide a proof of concept in the form of a scalable hypothesis testing method for CT, to enable quantifying uncertainty of possible PEs. In particular, we introduce a Bayesian Framework to quantify the uncertainty of an observed compact structure that can be identified as a PE. We assess the ability of the method to operate under high-noise environments and with insufficient data.

'Super Rehab': can we achieve coronary artery disease regression? A feasibility study protocol.

INTRODUCTION: Patients diagnosed with coronary artery disease (CAD) are currently treated with medications and lifestyle advice to reduce the likelihood of disease progression and risk of future major adverse cardiovascular events (MACE). Where obstructive disease is diagnosed, revascularisation may be considered to treat refractory symptoms. However, many patients with coexistent cardiovascular risk factors, particularly those with metabolic syndrome (MetS), remain at heightened risk of future MACE despite current management.Cardiac rehabilitation is offered to patients post-revascularisation, however, there is no definitive evidence demonstrating its benefit in a primary prevention setting. We propose that an intensive lifestyle intervention (Super Rehab, SR) incorporating high-intensity exercise, diet and behavioural change techniques may improve symptoms, outcomes, and enable CAD regression.This study aims to examine the feasibility of delivering a multicentre randomised controlled trial (RCT) testing SR for patients with CAD, in a primary prevention setting. METHODS AND ANALYSIS: This is a multicentre randomised controlled feasibility study of SR versus usual care in patients with CAD. The study aims to recruit 50 participants aged 18-75 across two centres. Feasibility will be assessed against rates of recruitment, retention and, in the intervention arm, attendance and adherence to SR. Qualitative interviews will explore trial experiences of study participants and practitioners. Variance of change in CAD across both arms of the study (assessed with serial CT coronary angiography) will inform the design and power of a future, multi-centre RCT. ETHICS AND DISSEMINATION: Ethics approval was granted by South West-Frenchay Research Ethics Committee (reference: 21/SW/0153, 18 January 2022). Study findings will be disseminated via presentations to relevant stakeholders, national and international conferences and open-access peer-reviewed research publications. TRIAL REGISTRATION NUMBER: ISRCTN14603929.

A Clinical Comparison of 2 Bronchial Blockers Versus Double-Lumen Tubes for One-Lung Ventilation.

OBJECTIVES: To compare the quality of lung collapse, time, and number of attempts required to achieve lung isolation, and incidence of intraoperative malpositioning between the EZ blocker (EZB), Fuji Uniblocker (UB), and the left-sided double lumen tube (DLT). DESIGN: Prospective, randomized clinical trial. SETTING: Single tertiary-level, university-affiliated hospital. PARTICIPANTS: Eighty-nine patients undergoing elective open thoracotomies or video-assisted thoracoscopic surgery. INTERVENTIONS: The 89 patients were randomized to receive a DLT, UB, or EZB for one-lung ventilation. MEASUREMENTS AND MAIN RESULTS: The quality of lung collapse at the time of pleural opening and 10 and 20 minutes thereafter were assessed by the surgeon using the Lung Collapse Score (LCS; 0 = no lung collapse to 10 = best lung collapse). The time and number of attempts required to achieve lung isolation and the number of repositions required during surgery were measured. Tracheobronchial tree measurements were performed by radiologists from preoperative computed tomography imaging. The surgeon remained blinded to the type of device used. Twenty-nine patients were randomized to the DLT group and 30 patients to each of the EZB and UB groups. The LCSs among the groups at pleural opening and 10 minutes after pleural opening were not significantly different (p = 0.34 and p = 0.08, respectively). However, at 20 minutes after the pleural opening, the LCSs were significantly different among groups (p = 0.02), with median scores being significantly lower for DLT (9 [IQR 8-9]) than for EZB (9 [IQR 9-10]; p = 0.04) and UB (9.5 [IQR 9-10]; p = 0.02). Lung isolation was achieved fastest in the DLT group (p < 0.01). The frequency of difficult placement did not significantly differ among groups, although it occurred most frequently in UB (n = 7; 23.3%). Intraoperative repositioning also occurred most often with the UB (n = 15; 50.0%). The EZB had the greatest number of cases requiring >2 repositions (n = 4, 13.3%). There were no differences between preoperative airway measurements and time to isolation or incidence of intraoperative repositioning among the groups. CONCLUSIONS: The LCS was comparable among the 3 devices until 20 minutes after pleural opening, when better scores were obtained in the bronchial blocker groups. Lung isolation was achieved fastest with the DLT. The EZB had the highest incidence of cases requiring >2 intraoperative repositions, mostly occurring in R-sided surgery. For L-sided surgery, the EZB performed equally to the UB. This suggests that using the EZB for R-sided video-assisted thoracoscopic surgery may be suboptimal. Preoperative airway dimensions did not correlate with time to achieve isolation or incidence of intraoperative malpositioning.

Assessing the role of an artificial intelligence assessment tool for thoracic aorta diameter on routine chest CT.

OBJECTIVE: To assess the diagnostic accuracy and clinical impact of automated artificial intelligence (AI) measurement of thoracic aorta diameter on routine chest CT. METHODS: A single-centre retrospective study involving three cohorts. 210 consecutive ECG-gated CT aorta scans (mean age 75 ± 13) underwent automated analysis (AI-Rad Companion Chest CT, Siemens) and were compared to a reference standard of specialist cardiothoracic radiologists for accuracy measuring aortic diameter. A repeated measures analysis tested reporting consistency in a second cohort (29 patients, mean age 61 ± 17) of immediate sequential pre-contrast and contrast CT aorta acquisitions. Potential clinical impact was assessed in a third cohort of 197 routine CT chests (mean age 66 ± 15) to document potential clinical impact. RESULTS: AI analysis produced a full report in 387/436 (89%) and a partial report in 421/436 (97%). Manual vs AI agreement was good to excellent (ICC 0.76-0.92). Repeated measures analysis of expert and AI reports for the ascending aorta were moderate to good (ICC 0.57-0.88). AI diagnostic performance crossed the threshold for maximally accepted limits of agreement (>5 mm) at the aortic root on ECG-gated CTs. AI newly identified aortic dilatation in 27% of patients on routine thoracic imaging with a specificity of 99% and sensitivity of 77%. CONCLUSION: AI has good agreement with expert readers at the mid-ascending aorta and has high specificity, but low sensitivity, at detecting dilated aortas on non-dedicated chest CTs. ADVANCES IN KNOWLEDGE: An AI tool may improve the detection of previously unknown thoracic aorta dilatation on chest CTs vs current routine reporting.

Deep-Learning for Epicardial Adipose Tissue Assessment With Computed Tomography: Implications for Cardiovascular Risk Prediction.

BACKGROUND: Epicardial adipose tissue (EAT) volume is a marker of visceral obesity that can be measured in coronary computed tomography angiograms (CCTA). The clinical value of integrating this measurement in routine CCTA interpretation has not been documented. OBJECTIVES: This study sought to develop a deep-learning network for automated quantification of EAT volume from CCTA, test it in patients who are technically challenging, and validate its prognostic value in routine clinical care. METHODS: The deep-learning network was trained and validated to autosegment EAT volume in 3,720 CCTA scans from the ORFAN (Oxford Risk Factors and Noninvasive Imaging Study) cohort. The model was tested in patients with challenging anatomy and scan artifacts and applied to a longitudinal cohort of 253 patients post-cardiac surgery and 1,558 patients from the SCOT-HEART (Scottish Computed Tomography of the Heart) Trial, to investigate its prognostic value. RESULTS: External validation of the deep-learning network yielded a concordance correlation coefficient of 0.970 for machine vs human. EAT volume was associated with coronary artery disease (odds ratio [OR] per SD increase in EAT volume: 1.13 [95% CI: 1.04-1.30]; P = 0.01), and atrial fibrillation (OR: 1.25 [95% CI: 1.08-1.40]; P = 0.03), after correction for risk factors (including body mass index). EAT volume predicted all-cause mortality (HR per SD: 1.28 [95% CI: 1.10-1.37]; P = 0.02), myocardial infarction (HR: 1.26 [95% CI:1.09-1.38]; P = 0.001), and stroke (HR: 1.20 [95% CI: 1.09-1.38]; P = 0.02) independently of risk factors in SCOT-HEART (5-year follow-up). It also predicted in-hospital (HR: 2.67 [95% CI: 1.26-3.73]; P ≤ 0.01) and long-term post-cardiac surgery atrial fibrillation (7-year follow-up; HR: 2.14 [95% CI: 1.19-2.97]; P ≤ 0.01). CONCLUSIONS: Automated assessment of EAT volume is possible in CCTA, including in patients who are technically challenging; it forms a powerful marker of metabolically unhealthy visceral obesity, which could be used for cardiovascular risk stratification.

Artificial Intelligence as a Diagnostic Tool in Non-Invasive Imaging in the Assessment of Coronary Artery Disease.

Coronary artery disease (CAD) remains a leading cause of mortality and morbidity worldwide, and it is associated with considerable economic burden. In an ageing, multimorbid population, it has become increasingly important to develop reliable, consistent, low-risk, non-invasive means of diagnosing CAD. The evolution of multiple cardiac modalities in this field has addressed this dilemma to a large extent, not only in providing information regarding anatomical disease, as is the case with coronary computed tomography angiography (CCTA), but also in contributing critical details about functional assessment, for instance, using stress cardiac magnetic resonance (S-CMR). The field of artificial intelligence (AI) is developing at an astounding pace, especially in healthcare. In healthcare, key milestones have been achieved using AI and machine learning (ML) in various clinical settings, from smartwatches detecting arrhythmias to retinal image analysis and skin cancer prediction. In recent times, we have seen an emerging interest in developing AI-based technology in the field of cardiovascular imaging, as it is felt that ML methods have potential to overcome some limitations of current risk models by applying computer algorithms to large databases with multidimensional variables, thus enabling the inclusion of complex relationships to predict outcomes. In this paper, we review the current literature on the various applications of AI in the assessment of CAD, with a focus on multimodality imaging, followed by a discussion on future perspectives and critical challenges that this field is likely to encounter as it continues to evolve in cardiology.

MRI-based strain measurements reflect morphological changes following myocardial infarction: A study on the UK Biobank cohort.

In a porcine experimental model of myocardial infarction, a localised, layer-specific, circumferential left ventricular strain metric has been shown to indicate chronic changes in ventricular function post-infarction more strongly than ejection fraction. This novel strain metric might therefore provide useful prognostic information clinically. In this study, existing clinical volume indices, global strains, and the novel, layer-specific strain were calculated for a large human cohort to assess variations in ventricular function and morphology with age, sex, and health status. Imaging and health data from the UK Biobank were obtained, including healthy volunteers and those with a history of cardiovascular illness. In total, 710 individuals were analysed and stratified by age, sex and health. Significant differences in all strain metrics were found between healthy and unhealthy populations, as well as between males and females. Significant differences in basal circumferential strain and global circumferential strain were found between healthy males and females, with males having smaller absolute values for both (all p ≤ 0.001). There were significant differences in the functional variables left ventricular ejection fraction, end-systolic volume, end-systolic volume index and mid-ventricular circumferential strain between healthy and unhealthy male cohorts aged 65-74 (all p ≤ 0.001). These results suggest that whilst regional circumferential strains may be useful clinically for assessing cardiovascular health, care must be taken to ensure critical values are indexed correctly to age and sex, due to the differences in these values observed here.

CT coronary angiography first prior to rapid access chest pain clinic review: a retrospective feasibility study.

OBJECTIVES: Since rapid access chest pain clinics (RACPC) were established to streamline stable chest pain assessment, CT coronary angiography (CTCA) has become the recommended investigation for patients without known coronary artery disease (CAD), with well-defined indications. This single-centre retrospective study assessed the feasibility of General Practice (GP)-led CTCA prior to RACPC. METHODS: RACPC pathway patients without pre-existing CAD electronic records were reviewed (September-October 2019). Feasibility assessments included appropriateness for RACPC, referral clinical data vs RACPC assessment for CTCA indication and safety, and a comparison of actual vs hypothetical pathways, timelines and hospital encounters. RESULTS: 106/172 patients screened met inclusion criteria (mean age 61 ± 14, 51% female). 102 (96%) referrals were 'appropriate'. No safety concerns were identified to preclude a GP-led CTCA strategy. The hypothetical pathway increased CTCA requests vs RACPC (84 vs 71), whilst improving adherence to guidelines and off-loading other services. 22% (23/106) had no CAD, representing cases where one hospital encounter may be sufficient. The hypothetical pathway would have reduced referral-to-diagnosis by at least a median of 27 days (interquartile range 14-33). CONCLUSION: A hypothetical GP-led CTCA pathway would have been feasible and safe in a real-world RACPC patient cohort without pre-existing CAD. This novel strategy would have increased referrals for CTCA, whilst streamlining patient pathways and improved NICE guidance adherence. ADVANCES IN KNOWLEDGE: GP-led CTCA is a feasible and safe pathway for patients without pre-existing CAD referred to RACPC, reducing hospital encounters required and may accelerate time to diagnosis. This approach may have implications and opportunities for other healthcare pathways.

Impact of an ultra-low dose unenhanced planning scan on CT coronary angiography scan length and effective radiation dose.

Objective: Imaged scan length (z-axis coverage) is a simple parameter that can reduce CT dose without compromising image quality. In CT coronary angiography (CTCA), z-axis coverage may be planned using non-contrast calcium score scan (CaCS) to identify the relevant coronary anatomy. However, standardised Agatston CaCS is acquired at 120 kV which adds a relatively high contribution to total study dose and CaCS is no longer routinely recommended in UK guidelines. We evaluate an ultra-low dose unenhanced planning scan on CTCA scan length and effective radiation dose. Methods: An ultra-low dose tin filter (Sn-filter) planning scan (100 kVp, maximum iterative reconstruction) was performed and used to plan the z-axis coverage on 48 consecutive CTCAs (62% men, 62 ± 13 years) compared with 47 CTCA planned using a localiser alone (46% men, 59 ± 12 years) between May and June 2019. Excess scanning beyond the ideal scan length was calculated for both groups. Estimations of radiation dose were also compared between the two groups. Results: Addition of an ultra-low dose unenhanced planning scan to CTCA protocol was associated with reduction in overscanning with no impact on image quality. There was no significant difference in total study effective dose with the addition of the planning scan, which had an average dose-length product of 3 mGy.cm. (total study dose: Protocol A 2.1 mSv vs Protocol B 2.2 mSv, p = 0.92). Conclusion: An ultra-low dose unenhanced planning scan facilitates optimal scan length for the diagnostic CTCA, reducing overscanning and preventing incomplete cardiac imaging with no significant dose penalty or impact on image quality. Advances in knowledge: An ultra-low dose CTCA planning is feasible and effective at optimising scan length.

Cancer symptom clusters in adult patients undergoing chemotherapy: A systematic review and meta-analysis protocol.

BACKGROUND: In oncology, the prevalence of symptoms is preferentially analyzed in isolation instead of being considered in clusters. However, clinical practice shows that symptoms rarely occur separately but rather form clusters that share common underlying mechanisms in terms of intensity and severity, creating a synergistic effect among them, which can even help predict the development of future symptoms. OBJECTIVE: To identify and gather evidence on the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. METHODS: This systematic review and meta-analysis protocol was developed in compliance with PRISMA-P. Observational and experimental study designs will be included. MEDLINE/PubMed, Cochrane Library, Embase, CINAHL, PsycINFO, Web of Science, Scopus, LILACS, clinical trials.gov-NIH, the British Library, Google Scholar, and preprints [medRXiv] will be searched with no restrictions on idioms, dates, or settings. Two investigators will independently select the studies, perform data extraction, and critically appraise the risk of bias of the included studies. Heterogeneity among the studies will be assessed using the I2 statistic. If meta-analysis was feasible, a random-effect model analysis will be carried out. For data analysis, the pooled effect will be estimated considering 95% confidence interval and α = 5%. In addition, the certainty of evidence will be rated based on Cochrane methods in accordance with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE). DISCUSSION: To the best of our knowledge, this systematic review and meta-analysis will be the first to identify and critically assess evidence regarding the prevalence, composition, severity, and predictors of cancer symptom clusters in adult cancer patients undergoing chemotherapy. We intend to provide health professionals with subsidies to reflect on a better understanding of symptom clusters in adult cancer patients, with the aim of contributing to the development of evidence-based therapeutic interventions and success in clinical practice. PROSPERO REGISTRATION NUMBER: CRD42021248406.

Constructing custom-made radiotranscriptomic signatures of vascular inflammation from routine CT angiograms: a prospective outcomes validation study in COVID-19.

BACKGROUND: Direct evaluation of vascular inflammation in patients with COVID-19 would facilitate more efficient trials of new treatments and identify patients at risk of long-term complications who might respond to treatment. We aimed to develop a novel artificial intelligence (AI)-assisted image analysis platform that quantifies cytokine-driven vascular inflammation from routine CT angiograms, and sought to validate its prognostic value in COVID-19. METHODS: For this prospective outcomes validation study, we developed a radiotranscriptomic platform that uses RNA sequencing data from human internal mammary artery biopsies to develop novel radiomic signatures of vascular inflammation from CT angiography images. We then used this platform to train a radiotranscriptomic signature (C19-RS), derived from the perivascular space around the aorta and the internal mammary artery, to best describe cytokine-driven vascular inflammation. The prognostic value of C19-RS was validated externally in 435 patients (331 from study arm 3 and 104 from study arm 4) admitted to hospital with or without COVID-19, undergoing clinically indicated pulmonary CT angiography, in three UK National Health Service (NHS) trusts (Oxford, Leicester, and Bath). We evaluated the diagnostic and prognostic value of C19-RS for death in hospital due to COVID-19, did sensitivity analyses based on dexamethasone treatment, and investigated the correlation of C19-RS with systemic transcriptomic changes. FINDINGS: Patients with COVID-19 had higher C19-RS than those without (adjusted odds ratio [OR] 2·97 [95% CI 1·43-6·27], p=0·0038), and those infected with the B.1.1.7 (alpha) SARS-CoV-2 variant had higher C19-RS values than those infected with the wild-type SARS-CoV-2 variant (adjusted OR 1·89 [95% CI 1·17-3·20] per SD, p=0·012). C19-RS had prognostic value for in-hospital mortality in COVID-19 in two testing cohorts (high [≥6·99] vs low [<6·99] C19-RS; hazard ratio [HR] 3·31 [95% CI 1·49-7·33], p=0·0033; and 2·58 [1·10-6·05], p=0·028), adjusted for clinical factors, biochemical biomarkers of inflammation and myocardial injury, and technical parameters. The adjusted HR for in-hospital mortality was 8·24 (95% CI 2·16-31·36, p=0·0019) in patients who received no dexamethasone treatment, but 2·27 (0·69-7·55, p=0·18) in those who received dexamethasone after the scan, suggesting that vascular inflammation might have been a therapeutic target of dexamethasone in COVID-19. Finally, C19-RS was strongly associated (r=0·61, p=0·00031) with a whole blood transcriptional module representing dysregulation of coagulation and platelet aggregation pathways. INTERPRETATION: Radiotranscriptomic analysis of CT angiography scans introduces a potentially powerful new platform for the development of non-invasive imaging biomarkers. Application of this platform in routine CT pulmonary angiography scans done in patients with COVID-19 produced the radiotranscriptomic signature C19-RS, a marker of cytokine-driven inflammation driving systemic activation of coagulation and responsible for adverse clinical outcomes, which predicts in-hospital mortality and might allow targeted therapy. FUNDING: Engineering and Physical Sciences Research Council, British Heart Foundation, Oxford BHF Centre of Research Excellence, Innovate UK, NIHR Oxford Biomedical Research Centre, Wellcome Trust, Onassis Foundation.

Assessing splenic switch-off in Adenosine stress CMR for patients with atrial fibrillation: a propensity-matched study.

OBJECTIVES: Splenic switch-off (SSO) is a validated indicator of adequate vasodilator stress unique to adenosine stress cardiac MR (CMR). Patients in atrial fibrillation (AF) may have a reduced adenosine response due to lower hyperaemic coronary flow reserve and may achieve SSO less frequently versus sinus rhythm (SR). METHODS: 1100 stress CMR studies were identified from a clinical CMR database (2016-2021). 70 patients in AF were propensity score matched to a SR group for age, sex, and body mass index. The adenosine dose administered, symptoms, heart-rate change and scan result were recorded. SSO was evaluated subjectively and semi-quantitatively via changes in splenic and myocardial signal intensity (SI) from rest to stress. RESULTS: SSO occurred significantly less frequently in AF than SR (34/70 [49%] vs 53/70 [76%], p = 0.003). Semi-quantitative assessment supported this, with a smaller splenic SI difference between stress and rest in AF vs SR (median splenic stress:rest peak SI ratio 0.92 [IQR:0.61-1.11] vs 0.56 [IQR:0.45-0.75], p < 0.001). A heart-rate increase >10 bpm predicted visual SSO in SR but not AF. Fewer patients in AF than SR had inducible ischaemia (9/70 [13%] vs 17/69 [25%], p = 0.058). This difference was not driven by inducible ischaemia rates in patients who did not achieve SSO (6/36 [17%] AF vs 4/17 [24%] SR, p = 0.403). CONCLUSIONS: SSO occurs significantly less frequently with AF. This may risk the under diagnosis of inducible ischaemia and requires further assessment. ADVANCES IN KNOWLEDGE: SSO, a validated marker of adequate stress in CMR, occurs significantly less frequently in the presence of AF, risking a suboptimal functional assessment of coronary disease.

Left ventricular active strain energy density is a promising new measure of systolic function.

The left ventricular ejection fraction does not accurately predict exercise capacity or symptom severity and has a limited role in predicting prognosis in heart failure. A better method of assessing ventricular performance is needed to aid understanding of the pathophysiological mechanisms and guide management in conditions such as heart failure. In this study, we propose two novel measures to quantify myocardial performance, the global longitudinal active strain energy (GLASE) and its density (GLASED) and compare them to existing measures in normal and diseased left ventricles. GLASED calculates the work done per unit volume of muscle (energy density) by combining information from myocardial strain and wall stress (contractile force per unit cross sectional area). Magnetic resonance images were obtained from 183 individuals forming four cohorts (normal, hypertension, dilated cardiomyopathy, and cardiac amyloidosis). GLASE and GLASED were compared with the standard ejection fraction, the corrected ejection fraction, myocardial strains, stroke work and myocardial forces. Myocardial shortening was decreased in all disease cohorts. Longitudinal stress was normal in hypertension, increased in dilated cardiomyopathy and severely decreased in amyloid heart disease. GLASE was increased in hypertension. GLASED was mildly reduced in hypertension (1.39 ± 0.65 kJ/m3), moderately reduced in dilated cardiomyopathy (0.86 ± 0.45 kJ/m3) and severely reduced in amyloid heart disease (0.42 ± 0.28 kJ/m3) compared to the control cohort (1.94 ± 0.49 kJ/m3). GLASED progressively decreased in the hypertension, dilated cardiomyopathy and cardiac amyloid cohorts indicating that mechanical work done and systolic performance is severely reduced in cardiac amyloid despite the relatively preserved ejection fraction. GLASED provides a new technique for assessing left ventricular myocardial health and contractile function.

Cerebrovascular Variants and the Role of the Selfish Brain in Young-Onset Hypertension.

BACKGROUND: Variants in the posterior anatomy of the cerebral circulation are associated with hypertension and lower cerebral blood flow in midlife (age ≈55 years); however, whether these variants are a result of aging or long-term exposure to high blood pressure is unclear. Additionally, the role these variants play in early onset of hypertension (<40 years) and poor cerebral perfusion in this population is unknown. METHODS: We retrospectively examined whether specific cerebrovascular variants (vertebral artery hypoplasia and absent/hypoplastic posterior communicating arteries (an incomplete posterior circle of Willis) measured via magnetic resonance angiography) were associated with a diagnosis of hypertension in 220 young adults (<40 years; n=164 primary hypertensive [mean age±SD, 32±6 years] and n=56 [30±6 years] normotensive adults). Whether cerebrovascular variants were associated with lower cerebral blood flow (phase-contrast angiography) was measured in the hypertensive group only (n=146). RESULTS: Binary logistic regression (adjusted for age, sex, and body mass index) showed that vertebral artery hypoplasia with an incomplete posterior circle of Willis was associated with hypertension diagnosis (P<0.001, odds ratio; 11.79 [95% CI, 3.34-41.58]). Vertebral artery hypoplasia plus an incomplete circle of Willis was associated with lower cerebral blood flow in young adults with hypertension (P=0.0172). CONCLUSIONS: Vertebral artery hypoplasia plus an incomplete posterior circle of Willis independently predicts hypertension in young adults suggesting that this variant is not acquired with aging into midlife. Importantly this variant combination was associated with lower cerebral perfusion, which may have long-term consequences on cerebrovascular health in young adults with hypertension.

Artificial intelligence can detect left ventricular dilatation on contrast-enhanced thoracic computer tomography relative to cardiac magnetic resonance imaging.

OBJECTIVES: To assess the diagnostic accuracy of an automated algorithm to detect left ventricular (LV) dilatation on non-ECG gated CT, using cardiac magnetic resonance (CMR) as reference standard. METHODS: Consecutive patients with contrast-enhanced CT thorax and CMR within 31 days (2016-2020) were analysed (n = 84). LV dilatation was defined against age-, sex- and body surface area-specific values for CMR. CTs underwent automated artificial intelligence(AI)-derived analysis that segmented ventricular chambers, presenting maximal LV diameter and volume. Area under the receiver operator curve (AUC-ROC) analysis identified CT thresholds with ≥90% sensitivity and highest specificity and ≥90% specificity with highest sensitivity. Youden's Index was used to identify thresholds with optimised sensitivity and specificity. RESULTS: Automated diameter analysis was feasible in 92% of cases (77/84; 45 men, age 61 ± 14 years, mean CT to CMR interval 10 ± 8 days). Relative to CMR as a reference standard, 45% had LV dilatation. In males, an automated LV diameter measurement of ≥55.5 mm was ≥90% specific for CMR-defined LV dilatation (positive predictive value (PPV) 85.7%, negative predictive value (NPV) 61.2%, accuracy 68.9%). In females, an LV diameter of ≥49.7 mm was ≥90% specific for CMR-defined LV dilatation (PPV 66.7%, NPV 73.1%, accuracy 71.9%). AI CT volumetry data did not significantly improve AUC performance. CONCLUSION: Fully automated AI-derived analysis LV dilatation on routine unselected non-gated contrast-enhanced CT thorax studies is feasible. We have defined thresholds for the detection of LV dilatation on CT relative to CMR, which could be used to routinely screen for dilated cardiomyopathy at the time of CT. ADVANCES IN KNOWLEDGE: We show, for the first time, that a fully-automated AI-derived analysis of maximal LV chamber axial diameter on non-ECG-gated thoracic CT is feasible in unselected real-world cases and that the derived measures can predict LV dilatation relative to cardiac magnetic resonance imaging, the non-invasive reference standard for determining cardiac chamber size. We have derived sex-specific cut-off values to screen for LV dilatation on routine contrast-enhanced thoracic CT. Future work should validate these thresholds and determine if technology can alter clinical outcomes in a cost-effective manner.

Screening success: A virtual MDT can reduce the number of patients requiring respiratory follow-up post-COVID-19 pneumonia in line with British Thoracic Society guidance.

Introduction and objectivesThe ongoing respiratory sequelae of COVID-19 pneumonia remain unclear, and the ideal follow-up of these patients is still a work in progress. We describe our experience of using a pre-follow-up multidisciplinary team (MDT) to decide the follow-up stream in patients hospitalised for COVID-19 pneumonia. METHODS: We reviewed all patients with a clinico-radiological diagnosis of COVID-19 admitted to hospital during a 3-month period and assigned a follow-up stream based on British Thoracic Society guidance. RESULTS: We changed the follow-up pathway in 71% (277/392) and refined the pathway in 67% (261/392) of indeterminate cases. We also created an automated process for the general practitioner to book follow-up imaging and will use this process going forward. CONCLUSION: These findings highlight the importance of the MDT review of cases with suspected COVID-19 pneumonia prior to clinic attendance to ensure appropriate patients are followed up and to optimise utilisation of outpatient imaging and clinics.

Consumption of mate Ilex paraguariensis: a folk beverage with antioxidant power against myocardial ischemic injury

The effects of the aqueous extract of Ilex paraguariensis (Ip)and the flavonoid quercetin were tested during the induction of in vivomyocardial ischemia/ reperfusion in Rattus norvegicus. The antioxidant power of the extract and quercetin were chemically determined. The experimental groups were: control, ischemia/reperfusion induction, Iporal treatment, Iporal treatment and ischemia /reperfusion, quercetin oral treatment, and quercetin oral treatment and ischemia/reperfusion. Rats were anesthetized with sodium thiopental and xylazine via intraperitoneal injection and subsequently underwent 15 minutes of ischemia followed by 15 minutes of reperfusion. Ischemia was promoted by tying the left anterior descending coronary artery. Areas of risk and infarction were stained by intravenous Evans blue and triphenyl tetrazolium chloride. Reactive oxygen species (ROS), antioxidant capacity against peroxylradicals, and lipid peroxidation of the myocardium were quantified. A significant reduction in areas of risk and infarction was detected in the ischemic myocardium treated with Ipand quercetin; ROS generation and lipid peroxidation were significantly reduced, and the antioxidant capacity was elevated. Oral administration of Ippromoted antioxidant benefits in the myocardium during ischemia and reperfusion, which reduced infarction. We suggest that Mate (a hot drink made from steeped dried leaves of Ip) consumption is a potential cardioprotective habit of indigenous people from southern South American countries, which must be better understood scientifically and ethnographically.

Vascular Thrombosis in Severe COVID-19 Requiring Extracorporeal Membrane Oxygenation: A Multicenter Study.

OBJECTIVES: Coronavirus disease 2019 has been reported to be a prothrombotic condition; however, multicenter data comparing this with other viral pneumonias in those requiring extracorporeal membrane oxygenation are lacking. We conducted a multicenter study using whole-body CT to examine the prevalence, severity, and nature of vascular complications in coronavirus disease 2019 in comparison with patients with other viral pneumonias. DESIGN: We analyzed whole-body CT scans for the presence of vascular thrombosis (defined as pulmonary artery thrombus, venous thrombus, systemic arterial thrombus, or end-organ infarct). The severity, distribution, and morphology of pulmonary artery thrombus were characterized. Competing risk cumulative incidence analysis was used to compare survival with discharge. SETTING: Three centers of the English national extracorporeal membrane oxygenation service. PATIENTS: Consecutive patients admitted with either coronavirus disease 2019 or noncoronavirus disease 2019 viral pneumonia admitted from January 2019. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: One-hundred thirty-six patients (45.2 ± 10.6 yr old, 39/146 [27%] female) requiring extracorporeal membrane oxygenation support underwent whole-body CT scans at admission. Of these, 86 had coronavirus disease 2019 pneumonia, and 50 had noncoronavirus disease 2019 viral pneumonia. Vascular thrombosis was seen more often in patients with coronavirus disease 2019 (odds ratio, 12.9 [95% CI 4.5-36.8]). In those with coronavirus disease 2019, 57 (73%) demonstrated pulmonary artery thrombus or pulmonary perfusion defects. Eighty-two percent of thrombus exhibited emboli-like morphology. The location of pulmonary artery thrombus and parenchymal perfusion defects was only concordant in 30% of cases. The risk of mortality was higher in those with coronavirus disease 2019 compared with noncoronavirus disease 2019 pneumonia (χ2 = 3.94; p = 0.047). Mortality was no different in coronavirus disease 2019 patients with or without vascular thrombosis (χ2 = 0.44; p = 0.51). CONCLUSIONS: In patients who received extracorporeal membrane oxygenation, coronavirus disease 2019 is associated with a higher prevalence of vascular thrombosis compared with noncoronavirus disease viral pneumonias. The pattern of pulmonary vascular changes suggests concurrent embolic disease and small vessel disease. Despite this, vascular thrombosis was not linked to poorer short-term prognosis in those with coronavirus disease 2019.