Zibotentan in Microvascular Angina: A Randomized, Placebo-Controlled, Crossover Trial.

Background: Microvascular angina is associated with dysregulation of the endothelin system and impairments in myocardial blood flow, exercise capacity, and health-related quality of life. The G allele of the noncoding single nucleotide polymorphism RS9349379 enhances expression of the endothelin-1 gene (EDN1) in human vascular cells, potentially increasing circulating concentrations of Endothelin-1 (ET-1). Whether zibotentan, an oral ET-A receptor selective antagonist, is efficacious and safe for the treatment of microvascular angina is unknown. Methods: Patients with microvascular angina were enrolled in this double-blind, placebo-controlled, sequential crossover trial of zibotentan (10 mg daily for 12 weeks). The trial population was enriched to ensure a G allele frequency of 50% for the RS9349379 single nucleotide polymorphism. Participants and investigators were blinded to genotype. The primary outcome was treadmill exercise duration (seconds) using the Bruce protocol. The primary analysis estimated the mean within-participant difference in exercise duration after treatment with zibotentan versus placebo. Results: A total of 118 participants (mean ±SD; years of age 63.5 [9.2 ]; 71 [60.2% ] females; 25 [21.2% ] with diabetes) were randomized. Among 103 participants with complete data, the mean exercise duration with zibotentan treatment compared with placebo was not different (between-treatment difference, -4.26 seconds [95 ] CI, -19.60 to 11.06] P=0.5871). Secondary outcomes showed no improvement with zibotentan. Zibotentan reduced blood pressure and increased plasma concentrations of ET-1. Adverse events were more common with zibotentan (60.2%) compared with placebo (14.4%; P<0.001). Conclusions: Among patients with microvascular angina, short-term treatment with a relatively high dose (10 mg daily) of zibotentan was not beneficial. Target-related adverse effects were common.

Occult coronary microvascular dysfunction and ischemic heart disease in patients with diabetes and heart failure.

BACKGROUND: Patients with diabetes mellitus (DM) and heart failure (HF) have worse outcomes than normoglycemic HF patients. Cardiovascular magnetic resonance (CMR) can identify ischemic heart disease (IHD) and quantify coronary microvascular dysfunction (CMD) using myocardial perfusion reserve (MPR). We aimed to quantify the extent of silent IHD and CMD in patients with DM presenting with HF. METHODS: Prospectively recruited outpatients undergoing assessment into the etiology of HF underwent in-line quantitative perfusion CMR for calculation of stress and rest myocardial blood flow (MBF) and MPR. Exclusions included angina or history of IHD. Patients were followed up (median 3.0 years) for major adverse cardiovascular events (MACE). RESULTS: Final analysis included 343 patients (176 normoglycemic, 84 with pre-diabetes, and 83 with DM). Prevalence of silent IHD was highest in DM 31% ( 26/83), then pre-diabetes 20% (17/84) then normoglycemia 17%, ( 30/176). Stress MBF was lowest in DM (1.53 ± 0.52), then pre-diabetes (1.59 ± 0.54) then normoglycemia (1.83 ± 0.62). MPR was lowest in DM (2.37 ± 0.85) then pre-diabetes (2.41 ± 0.88) then normoglycemia (2.61 ± 0.90). During follow-up, 45 patients experienced at least one MACE. On univariate Cox regression analysis, MPR and presence of silent IHD were both associated with MACE. However, after correction for HbA1c, age, and left ventricular ejection fraction, the associations were no longer significant. CONCLUSION: Patients with DM and HF had higher prevalence of silent IHD, more evidence of CMD, and worse cardiovascular outcomes than their non-diabetic counterparts. These findings highlight the potential value of CMR for the assessment of silent IHD and CMD in patients with DM presenting with HF.

Clinical Significance of Myocardial Injury in Patients Hospitalized for COVID-19: A Prospective, Multicenter, Cohort Study.

BACKGROUND: Hospitalized COVID-19 patients with troponin elevation have a higher prevalence of cardiac abnormalities than control individuals. However, the progression and impact of myocardial injury on COVID-19 survivors remain unclear. OBJECTIVES: This study sought to evaluate myocardial injury in COVID-19 survivors with troponin elevation with baseline and follow-up imaging and to assess medium-term outcomes. METHODS: This was a prospective, longitudinal cohort study in 25 United Kingdom centers (June 2020 to March 2021). Hospitalized COVID-19 patients with myocardial injury underwent cardiac magnetic resonance (CMR) scans within 28 days and 6 months postdischarge. Outcomes were tracked for 12 months, with quality of life surveys (EuroQol-5 Dimension and 36-Item Short Form surveys) taken at discharge and 6 months. RESULTS: Of 342 participants (median age: 61.3 years; 71.1% male) with baseline CMR, 338 had a 12-month follow-up, 235 had a 6-month CMR, and 215 has baseline and follow-up quality of life surveys. Of 338 participants, within 12 months, 1.2% died; 1.8% had new myocardial infarction, acute coronary syndrome, or coronary revascularization; 0.8% had new myopericarditis; and 3.3% had other cardiovascular events requiring hospitalization. At 6 months, there was a minor improvement in left ventricular ejection fraction (1.8% ± 1.0%; P < 0.001), stable right ventricular ejection fraction (0.4% ± 0.8%; P = 0.50), no change in myocardial scar pattern or volume (P = 0.26), and no imaging evidence of continued myocardial inflammation. All pericardial effusions (26 of 26) resolved, and most pneumonitis resolved (95 of 101). EuroQol-5 Dimension scores indicated an overall improvement in quality of life (P < 0.001). CONCLUSIONS: Myocardial injury in severe hospitalized COVID-19 survivors is nonprogressive. Medium-term outcomes show a low incidence of major adverse cardiovascular events and improved quality of life. (COVID-19 Effects on the Heart; ISRCTN58667920).

In Vivo Formation of Adrenal Organoids in a Novel Porcine Model of Adrenocortical Cell Transplantation.

Recognizing the limitations of current therapies for Addison's disease, novel treatments that replicate dynamic physiologic corticosteroid secretion, under control of ACTH, are required. The aim of these experiments was to evaluate the feasibility of adrenocortical cell transplantation (ACT) in a large animal model, adapting methods successfully used for intracutaneous pancreatic islet cell transplantation, using a fully biodegradable temporizing matrix. Autologous porcine ACT was undertaken by bilateral adrenalectomy, cell isolation, culture, and intracutaneous injection into a skin site preprepared using a biodegradable temporizing matrix (BTM) foam. Hydrocortisone support was provided during adrenocortical cell engraftment and weaned as tolerated. Blood adrenocortical hormone concentrations were monitored, and the transplant site was examined at endpoint. Outcome measures included cellular histochemistry, systemic hormone production, and hydrocortisone independence. Transplanted adrenocortical cells showed a capability to survive and proliferate within the intracutaneous site and an ability to self-organize into discrete tissue organoids with features of the normal adrenal histologic architecture. Interpretation of systemic hormone levels was confounded by the identification of accessory adrenals and regenerative cortical tissue within the adrenal bed postmortem. Corticosteroids were unable to be completely ceased. ACT in a large animal model has not previously been attempted, yet it is an important step toward clinical translation. These results demonstrate rhe potential for ACT based on the development of adrenal organoids at the BTM site. However, the inability to achieve clinically relevant systemic hormone production suggests insufficient function, likely attributable to insufficient cells through delivered dose and subsequent proliferation.

Development and validation of AI-derived segmentation of four-chamber cine cardiac magnetic resonance.

BACKGROUND: Cardiac magnetic resonance (CMR) in the four-chamber plane offers comprehensive insight into the volumetrics of the heart. We aimed to develop an artificial intelligence (AI) model of time-resolved segmentation using the four-chamber cine. METHODS: A fully automated deep learning algorithm was trained using retrospective multicentre and multivendor data of 814 subjects. Validation, reproducibility, and mortality prediction were evaluated on an independent cohort of 101 subjects. RESULTS: The mean age of the validation cohort was 54 years, and 66 (65%) were males. Left and right heart parameters demonstrated strong correlations between automated and manual analysis, with a ρ of 0.91-0.98 and 0.89-0.98, respectively, with minimal bias. All AI four-chamber volumetrics in repeatability analysis demonstrated high correlation (ρ = 0.99-1.00) and no bias. Automated four-chamber analysis underestimated both left ventricular (LV) and right ventricular (RV) volumes compared to ground-truth short-axis cine analysis. Two correction factors for LV and RV four-chamber analysis were proposed based on systematic bias. After applying the correction factors, a strong correlation and minimal bias for LV volumetrics were observed. During a mean follow-up period of 6.75 years, 16 patients died. On stepwise multivariable analysis, left atrial ejection fraction demonstrated an independent association with death in both manual (hazard ratio (HR) = 0.96, p = 0.003) and AI analyses (HR = 0.96, p < 0.001). CONCLUSION: Fully automated four-chamber CMR is feasible, reproducible, and has the same real-world prognostic value as manual analysis. LV volumes by four-chamber segmentation were comparable to short-axis volumetric assessment. TRIALS REGISTRATION: ClinicalTrials.gov: NCT05114785. RELEVANCE STATEMENT: Integrating fully automated AI in CMR promises to revolutionise clinical cardiac assessment, offering efficient, accurate, and prognostically valuable insights for improved patient care and outcomes. KEY POINTS: • Four-chamber cine sequences remain one of the most informative acquisitions in CMR examination. • This deep learning-based, time-resolved, fully automated four-chamber volumetric, functional, and deformation analysis solution. • LV and RV were underestimated by four-chamber analysis compared to ground truth short-axis segmentation. • Correction bias for both LV and RV volumes by four-chamber segmentation, minimises the systematic bias.

Liraglutide Improves Myocardial Perfusion and Energetics and Exercise Tolerance in Patients With Type 2 Diabetes.

BACKGROUND: Type 2 diabetes (T2D) is characterized by insulin resistance (IR) and dysregulated insulin secretion. Glucagon-like peptide-1 receptor agonist liraglutide promotes insulin secretion, whereas thiazolidinedione-pioglitazone decreases IR. OBJECTIVES: This study aimed to compare the efficacies of increasing insulin secretion vs decreasing IR strategies for improving myocardial perfusion, energetics, and function in T2D via an open-label randomized crossover trial. METHODS: Forty-one patients with T2D (age 63 years [95% CI: 59-68 years], 27 [66%] male, body mass index 27.8 kg/m2) [95% CI: 26.1-29.5 kg/m2)]) without cardiovascular disease were randomized to liraglutide or pioglitazone for a 16-week treatment followed by an 8-week washout and a further 16-week treatment with the second trial drug. Participants underwent rest and dobutamine stress 31phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance for measuring the myocardial energetics index phosphocreatine to adenosine triphosphate ratio, myocardial perfusion (rest, dobutamine stress myocardial blood flow, and myocardial perfusion reserve), left ventricular (LV) volumes, systolic and diastolic function (mitral in-flow E/A ratio), before and after treatment. The 6-minute walk-test was used for functional assessments. RESULTS: Pioglitazone treatment resulted in significant increases in LV mass (96 g [95% CI: 68-105 g] to 105 g [95% CI: 74-115 g]; P = 0.003) and mitral-inflow E/A ratio (1.04 [95% CI: 0.62-1.21] to 1.34 [95% CI: 0.70-1.54]; P = 0.008), and a significant reduction in LV concentricity index (0.79 mg/mL [95% CI: 0.61-0.85 mg/mL] to 0.73 mg/mL [95% CI: 0.56-0.79 mg/mL]; P = 0.04). Liraglutide treatment increased stress myocardial blood flow (1.62 mL/g/min [95% CI: 1.19-1.75 mL/g/min] to 2.08 mL/g/min [95% CI: 1.57-2.24 mL/g/min]; P = 0.01) and myocardial perfusion reserve (2.40 [95% CI: 1.55-2.68] to 2.90 [95% CI: 1.83-3.18]; P = 0.01). Liraglutide treatment also significantly increased the rest (1.47 [95% CI: 1.17-1.58] to 1.94 [95% CI: 1.52-2.08]; P =0.00002) and stress phosphocreatine to adenosine triphosphate ratio (1.32 [95% CI: 1.05-1.42] to 1.58 [95% CI: 1.19-1.71]; P = 0.004) and 6-minute walk distance (488 m [95% CI: 458-518 m] to 521 m [95% CI: 481-561 m]; P = 0.009). CONCLUSIONS: Liraglutide treatment resulted in improved myocardial perfusion, energetics, and 6-minute walk distance in patients with T2D, whereas pioglitazone showed no effect on these parameters (Lean-DM [Targeting Beta-cell Failure in Lean Patients With Type 2 Diabetes]; NCT04657939).

Regression of cardiac angiosarcoma in a 17-year-old: a percutaneous biopsy effect.

BACKGROUND: Cardiac angiosarcoma is a very rare and aggressive primary cardiac tumor associated with poor prognosis. Diagnosis is often delayed due to non-specific symptoms, with most cases involving metastases at the time of diagnosis. We describe a unique case of apparent tumor regression of cardiac angiosarcoma post percutaneous biopsy. CASE PRESENTATION: A young male was admitted with suspected pericarditis. Echocardiogram revealed a pericardial mass. Cardiovascular magnetic resonance (CMR) suggested primary cardiac malignancy. Percutaneous biopsy was inconclusive, with subsequent CMR demonstrating apparent tumor regression. Interval imaging revealed further tumor growth, and surgical biopsy revealed primary cardiac angiosarcoma (PCAS). Causes of tumor regression following percutaneous biopsy are discussed. CONCLUSIONS: Cases of suspected primary cardiac malignancy require careful follow up with serial multimodality imaging. Percutaneous biopsy effects should be considered in cases of tumor regression, and serial imaging should be planned afterwards.

Feasibility of a new 'balanced binocular viewing' treatment for unilateral amblyopia in children aged 3-8 years (BALANCE): results of a phase 2a randomised controlled feasibility trial.

OBJECTIVES: This study aimed to evaluate the safety of dichoptic balanced binocular viewing (BBV) for amblyopia in children, plus feasibility, adherence, acceptability, trial methodology and clinical measures of visual function. DESIGN: We carried out an observer-masked parallel-group phase 2a feasibility randomised controlled trial. SETTING: Two study sites, a secondary/tertiary and a community site. PARTICIPANTS: We enrolled 32 children aged 3-8 years with unilateral amblyopia who had completed optical adaptation where indicated. 20 children attended the 16-week exit visit (retention 63%). INTERVENTIONS: Children were randomised to BBV (movies customised to interocular acuity difference at baseline) for 1 hour a day (active intervention) or standard management as per parental choice (part-time occlusion or atropine blurring, control). All interventions were used at home, daily for 16 weeks. PRIMARY OUTCOME MEASURE: 'VacMan suppression test' of interocular balance at 16 weeks from randomisation. SECONDARY OUTCOME MEASURES: feasibility outcomes (recruitment and retention ratios, adherence with the allocated intervention); safety outcomes at other time points (changes in prevalence of diplopia, manifest strabismus, suppression/interocular balance on a range of tests); efficacy outcomes (clinical measures of visual function, such as best-corrected visual acuity, BCVA). Outcome measures were identical to those planned in the protocol. RESULTS: Primary outcome: At baseline, values for the interocular balance point were higher (indicating greater suppression of the amblyopic eye) in the occlusion group than in the BBV group. These values shifted downwards on average for the occlusion group, significantly decreasing from baseline to week 16 (t8=4.49, p=0.002). Balance values did not change between baseline and week 16 for the BBV group (t9=-0.82, p=0.435). At 16 weeks, there was no statistical difference in interocular balance/suppression change over time between the two arms. The difference at follow-up between the arms, adjusted for baseline, was -0.02 (95% CI -0.28 to 0.23, p=0.87). FEASIBILITY: We prescreened 144 records of potentially eligible children. Between 28 October 2019 and 31 July 2021, including an interruption due to the COVID-19 pandemic, 32 children were screened and randomised (recruitment rate 22%), 16 to BBV and 16 to standard treatment. 20 children attended the 16-week exit visit (retention 63%). Mean adherence with BBV as proportion of viewing time prescribed was 56.1% (SD36) at 8 and 57.9% (SD 30.2) at 16 weeks. Mean adherence with prescribed occlusion time was 90.1% (SD 19.7) at 8 and 59.2% (SD 24.8) at 16 weeks. SECONDARY SAFETY/EFFICACY OUTCOMES: One child in the BBV arm reported transient double vision, which resolved; two reported headaches, which led to withdrawal. BCVA improved from mean 0.47 (SD0.18) logMAR at randomisation to 0.26 (0.14) with standard treatment, and from 0.55 (0.28) to 0.32 (0.26) with BBV. Outcomes at 16 weeks did not differ between treatments. PARTICIPANT EXPERIENCE: Families were generally positive about BBV, but families found both patching and BBV difficult to integrate into family routines. CONCLUSIONS: Recruitment rates indicate that a future phase 3 trial will require multiple sites or a longer enrolment period. Retention and adherence rates were lower than anticipated, which will influence future study designs. Dichoptic treatment may be equal to occlusion treatment in safety and efficacy; headaches may lead to discontinuation. Integration into family routines may constitute a barrier to implementation. TRIAL REGISTRATION NUMBER: NCT03754153.

Pulmonary transit time is a predictor of outcomes in heart failure: a cardiovascular magnetic resonance first-pass perfusion study.

BACKGROUND: Pulmonary transit time (PTT) can be measured automatically from arterial input function (AIF) images of dual sequence first-pass perfusion imaging. PTT has been validated against invasive cardiac catheterisation correlating with both cardiac output and left ventricular filling pressure (both important prognostic markers in heart failure). We hypothesized that prolonged PTT is associated with clinical outcomes in patients with heart failure. METHODS: We recruited outpatients with a recent diagnosis of non-ischaemic heart failure with left ventricular ejection fraction (LVEF) < 50% on referral echocardiogram. Patients were followed up by a review of medical records for major adverse cardiovascular events (MACE) defined as all-cause mortality, heart failure hospitalization, ventricular arrhythmia, stroke or myocardial infarction. PTT was measured automatically from low-resolution AIF dynamic series of both the LV and RV during rest perfusion imaging, and the PTT was measured as the time (in seconds) between the centroid of the left (LV) and right ventricle (RV) indicator dilution curves. RESULTS: Patients (N = 294) were followed-up for median 2.0 years during which 37 patients (12.6%) had at least one MACE event. On univariate Cox regression analysis there was a significant association between PTT and MACE (Hazard ratio (HR) 1.16, 95% confidence interval (CI) 1.08-1.25, P = 0.0001). There was also significant association between PTT and heart failure hospitalisation (HR 1.15, 95% CI 1.02-1.29, P = 0.02) and moderate correlation between PTT and N-terminal pro B-type natriuretic peptide (NT-proBNP, r = 0.51, P < 0.001). PTT remained predictive of MACE after adjustment for clinical and imaging factors but was no longer significant once adjusted for NT-proBNP. CONCLUSIONS: PTT measured automatically during CMR perfusion imaging in patients with recent onset non-ischaemic heart failure is predictive of MACE and in particular heart failure hospitalisation. PTT derived in this way may be a non-invasive marker of haemodynamic congestion in heart failure and future studies are required to establish if prolonged PTT identifies those who may warrant closer follow-up or medicine optimisation to reduce the risk of future adverse events.

CMR characterization of patients with heart failure and left bundle branch block.

Aims: We aimed to identify the distinctive cardiovascular magnetic resonance (CMR) features of patients with left bundle branch block (LBBB) and heart failure with reduced ejection fraction (HFrEF) of presumed non-ischaemic aetiology. The secondary aim was to determine whether these individuals exhibit characteristics that could potentially serve as predictors of left ventricular ejection fraction (LVEF) recovery as compared with patients without LBBB. Methods and results: We prospectively recruited patients with HFrEF (LVEF ≤ 40%) on echocardiography who were referred for early CMR examination. Patients with an established diagnosis of coronary artery disease and known structural or congenital heart disease were excluded. LV recovery was defined as achieving ≥10% absolute improvement to ≥40% in LVEF between baseline evaluation to CMR. A total of 391 patients were recruited including 115 (29.4%) with LBBB. Compared with HF patients without LBBB, those with LBBB exhibited larger left ventricles and smaller right ventricles, but no differences were observed with respect to LVEF (35.8 ± 12 vs. 38 ± 12%, P = 0.105). The overall rate of LV recovery from baseline echocardiogram to CMR (70 [42-128] days) was not significantly different between LBBB and non-LBBB patients (27.8% vs. 31.5%, P = 0.47). Reduced LVEF remained an independent predictor of LV non-recovery only in patients with LBBB. Conclusion: Patients presenting with HFrEF and LBBB had larger LV cavities and smaller RV cavities than those without LBBB but no difference in prevalence of scar or ischaemia. The rates of LV recovery were similar between both groups, which supports current guidelines to defer device therapy until 3-6 months of guideline-directed medical therapy, rather than early CMR and device implantation.

Sex differences in coronary atherosclerotic plaque activity using 18F-sodium fluoride positron emission tomography.

INTRODUCTION: There are sex differences in the extent, severity, and outcomes of coronary artery disease. We aimed to assess the influence of sex on coronary atherosclerotic plaque activity measured using coronary 18F-sodium fluoride (18F-NaF) positron emission tomography (PET), and to determine whether 18F-NaF PET has prognostic value in both women and men. METHODS: In a post-hoc analysis of observational cohort studies of patients with coronary atherosclerosis who had undergone 18F-NaF PET CT angiography, we compared the coronary microcalcification activity (CMA) in women and men. RESULTS: Baseline 18F-NaF PET CT angiography was available in 999 participants (151 (15%) women) with 4282 patient-years of follow-up. Compared to men, women had lower coronary calcium scores (116 [interquartile range, 27-434] versus 205 [51-571] Agatston units; p = 0.002) and CMA values (0.0 [0.0-1.12] versus 0.53 [0.0-2.54], p = 0.01). Following matching for plaque burden by coronary calcium scores and clinical comorbidities, there was no sex-related difference in CMA values (0.0 [0.0-1.12] versus 0.0 [0.0-1.23], p = 0.21) and similar proportions of women and men had no 18F-NaF uptake (53.0% (n = 80) and 48.3% (n = 73); p = 0.42), or CMA values > 1.56 (21.8% (n = 33) and 21.8% (n = 33); p = 1.00). Over a median follow-up of 4.5 [4.0-6.0] years, myocardial infarction occurred in 6.6% of women (n = 10) and 7.8% of men (n = 66). Coronary microcalcification activity greater than 0 was associated with a similarly increased risk of myocardial infarction in both women (HR: 3.83; 95% CI:1.10-18.49; p = 0.04) and men (HR: 5.29; 95% CI:2.28-12.28; p < 0.001). CONCLUSION: Although men present with more coronary atherosclerotic plaque than women, increased plaque activity is a strong predictor of future myocardial infarction regardless of sex.

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.

Long COVID and cardiovascular disease: a prospective cohort study.

BACKGROUND: Pre-existing cardiovascular disease (CVD) or cardiovascular risk factors have been associated with an increased risk of complications following hospitalisation with COVID-19, but their impact on the rate of recovery following discharge is not known. OBJECTIVES: To determine whether the rate of patient-perceived recovery following hospitalisation with COVID-19 was affected by the presence of CVD or cardiovascular risk factors. METHODS: In a multicentre prospective cohort study, patients were recruited following discharge from the hospital with COVID-19 undertaking two comprehensive assessments at 5 months and 12 months. Patients were stratified by the presence of either CVD or cardiovascular risk factors prior to hospitalisation with COVID-19 and compared with controls with neither. Full recovery was determined by the response to a patient-perceived evaluation of full recovery from COVID-19 in the context of physical, physiological and cognitive determinants of health. RESULTS: From a total population of 2545 patients (38.8% women), 472 (18.5%) and 1355 (53.2%) had CVD or cardiovascular risk factors, respectively. Compared with controls (n=718), patients with CVD and cardiovascular risk factors were older and more likely to have had severe COVID-19. Full recovery was significantly lower at 12 months in patients with CVD (adjusted OR (aOR) 0.62, 95% CI 0.43 to 0.89) and cardiovascular risk factors (aOR 0.66, 95% CI 0.50 to 0.86). CONCLUSION: Patients with CVD or cardiovascular risk factors had a delayed recovery at 12 months following hospitalisation with COVID-19. Targeted interventions to reduce the impact of COVID-19 in patients with cardiovascular disease remain an unmet need. TRAIL REGISTRATION NUMBER: ISRCTN10980107.

Coronary Atherosclerotic Plaque Activity and Risk of Myocardial Infarction.

BACKGROUND: Total coronary atherosclerotic plaque activity across the entire coronary arterial tree is associated with patient-level clinical outcomes. OBJECTIVES: We aimed to investigate whether vessel-level coronary atherosclerotic plaque activity is associated with vessel-level myocardial infarction. METHODS: In this secondary analysis of an international multicenter study of patients with recent myocardial infarction and multivessel coronary artery disease, we assessed vessel-level coronary atherosclerotic plaque activity using coronary 18F-sodium fluoride positron emission tomography to identify vessel-level myocardial infarction. RESULTS: Increased 18F-sodium fluoride uptake was found in 679 of 2,094 coronary arteries and 414 of 691 patients. Myocardial infarction occurred in 24 (4%) vessels with increased coronary atherosclerotic plaque activity and in 25 (2%) vessels without increased coronary atherosclerotic plaque activity (HR: 2.08; 95% CI: 1.16-3.72; P = 0.013). This association was not demonstrable in those treated with coronary revascularization (HR: 1.02; 95% CI: 0.47-2.25) but was notable in untreated vessels (HR: 3.86; 95% CI: 1.63-9.10; Pinteraction = 0.024). Increased coronary atherosclerotic plaque activity in multiple coronary arteries was associated with heightened patient-level risk of cardiac death or myocardial infarction (HR: 2.43; 95% CI: 1.37-4.30; P = 0.002) as well as first (HR: 2.19; 95% CI: 1.18-4.06; P = 0.013) and total (HR: 2.50; 95% CI: 1.42-4.39; P = 0.002) myocardial infarctions. CONCLUSIONS: In patients with recent myocardial infarction and multivessel coronary artery disease, coronary atherosclerotic plaque activity prognosticates individual coronary arteries and patients at risk for myocardial infarction.

Mitral regurgitation assessment by cardiovascular magnetic resonance imaging during continuous in-scanner exercise: a feasibility study.

PURPOSE: Exercise imaging using current modalities can be challenging. This was patient focused study to establish the feasibility and reproducibility of exercise-cardiovascular magnetic resonance imaging (EX-CMR) acquired during continuous in-scanner exercise in asymptomatic patients with primary mitral regurgitation (MR). METHODS: This was a prospective, feasibility study. Biventricular volumes/function, aortic flow volume, MR volume (MR-Rvol) and regurgitant fraction (MR-RF) were assessed at rest and during low- (Low-EX) and moderate-intensity exercise (Mod-EX) in asymptomatic patients with primary MR. RESULTS: Twenty-five patients completed EX-CMR without complications. Whilst there were no significant changes in the left ventricular (LV) volumes, there was a significant increase in the LVEF (rest 63 ± 5% vs. Mod-EX 68 ± 6%;p = 0.01). There was a significant reduction in the right ventricular (RV) end-systolic volume (rest 68 ml(60-75) vs. Mod-EX 46 ml(39-59);p < 0.001) and a significant increase in the RV ejection fraction (rest 55 ± 5% vs. Mod-EX 65 ± 8%;p < 0.001). Whilst overall, there were no significant group changes in the MR-Rvol and MR-RF, individual responses were variable, with MR-Rvol increasing by ≥ 15 ml in 4(16%) patients and decreasing by ≥ 15 ml in 9(36%) of patients. The intra- and inter-observer reproducibility of LV volumes and aortic flow measurements were excellent, including at Mod-EX. CONCLUSION: EX-CMR is feasible and reproducible in patients with primary MR. During exercise, there is an increase in the LV and RV ejection fraction, reduction in the RV end-systolic volume and a variable response of MR-Rvol and MR-RF. Understanding the individual variability in MR-Rvol and MR-RF during physiological exercise may be clinically important.

The disruptive role of LRG1 on the vasculature and perivascular microenvironment.

The establishment of new blood vessels, and their subsequent stabilization, is a critical process that facilitates tissue growth and organ development. Once established, vessels need to diversify to meet the specific needs of the local tissue and to maintain homeostasis. These processes are tightly regulated and fundamental to normal vessel and tissue function. The mechanisms that orchestrate angiogenesis and vessel maturation have been widely studied, with signaling crosstalk between endothelium and perivascular cells being identified as an essential component. In disease, however, new vessels develop abnormally, and existing vessels lose their specialization and function, which invariably contributes to disease progression. Despite considerable research into the vasculopathic mechanisms in disease, our knowledge remains incomplete. Accordingly, the identification of angiocrine and angiopathic molecules secreted by cells within the vascular microenvironment, and their effect on vessel behaviour, remains a major research objective. Over the last decade the secreted glycoprotein leucine-rich α-2 glycoprotein 1 (LRG1), has emerged as a significant vasculopathic molecule, stimulating defective angiogenesis, and destabilizing the existing vasculature mainly, but not uniquely, by altering both canonical and non-canonical TGF-ß signaling in a highly cell and context dependent manner. Whilst LRG1 does not possess any overt homeostatic role in vessel development and maintenance, growing evidence provides a compelling case for LRG1 playing a pleiotropic role in disrupting the vasculature in many disease settings. Thus, LRG1 has now been reported to damage vessels in various disorders including cancer, diabetes, chronic kidney disease, ocular disease, and lung disease and the signaling processes that drive this dysfunction are being defined. Moreover, therapeutic targeting of LRG1 has been widely proposed to re-establish a quiescent endothelium and normalized vasculature. In this review, we consider the current status of our understanding of the role of LRG1 in vascular pathology, and its potential as a therapeutic target.

Carbon monoxide as a cellular protective agent in a swine model of cardiac arrest protocol.

Out-of-hospital cardiac arrest (OHCA) affects over 360,000 adults in the United States each year with a 50-80% mortality prior to reaching medical care. Despite aggressive supportive care and targeted temperature management (TTM), half of adults do not live to hospital discharge and nearly one-third of survivors have significant neurologic injury. The current treatment approach following cardiac arrest resuscitation consists primarily of supportive care and possible TTM. While these current treatments are commonly used, mortality remains high, and survivors often develop lasting neurologic and cardiac sequela well after resuscitation. Hence, there is a critical need for further therapeutic development of adjunctive therapies. While select therapeutics have been experimentally investigated, one promising agent that has shown benefit is CO. While CO has traditionally been thought of as a cellular poison, there is both experimental and clinical evidence that demonstrate benefit and safety in ischemia with lower doses related to improved cardiac/neurologic outcomes. While CO is well known for its poisonous effects, CO is a generated physiologically in cells through the breakdown of heme oxygenase (HO) enzymes and has potent antioxidant and anti-inflammatory activities. While CO has been studied in myocardial infarction itself, the role of CO in cardiac arrest and post-arrest care as a therapeutic is less defined. Currently, the standard of care for post-arrest patients consists primarily of supportive care and TTM. Despite current standard of care, the neurological prognosis following cardiac arrest and return of spontaneous circulation (ROSC) remains poor with patients often left with severe disability due to brain injury primarily affecting the cortex and hippocampus. Thus, investigations of novel therapies to mitigate post-arrest injury are clearly warranted. The primary objective of this proposed study is to combine our expertise in swine models of CO and cardiac arrest for future investigations on the cellular protective effects of low dose CO. We will combine our innovative multi-modal diagnostic platform to assess cerebral metabolism and changes in mitochondrial function in swine that undergo cardiac arrest with therapeutic application of CO.

The resolution of face perception varies systematically across the visual field.

Visual abilities tend to vary predictably across the visual field-for simple low-level stimuli, visibility is better along the horizontal vs. vertical meridian and in the lower vs. upper visual field. In contrast, face perception abilities have been reported to show either distinct or entirely idiosyncratic patterns of variation in peripheral vision, suggesting a dissociation between the spatial properties of low- and higher-level vision. To assess this link more clearly, we extended methods used in low-level vision to develop an acuity test for face perception, measuring the smallest size at which facial gender can be reliably judged in peripheral vision. In 3 experiments, we show the characteristic inversion effect, with better acuity for upright faces than inverted, demonstrating the engagement of high-level face-selective processes in peripheral vision. We also observe a clear advantage for gender acuity on the horizontal vs. vertical meridian and a smaller-but-consistent lower- vs. upper-field advantage. These visual field variations match those of low-level vision, indicating that higher-level face processing abilities either inherit or actively maintain the characteristic patterns of spatial selectivity found in early vision. The commonality of these spatial variations throughout the visual hierarchy means that the location of faces in our visual field systematically influences our perception of them.

Approaches and experiences implementing remote, electronic consent at the Leeds Clinical Trials Research Unit.

BACKGROUND: Use of electronic methods to support informed consent ('eConsent') is increasingly popular in clinical research. This commentary reports the approach taken to implement electronic consent methods and subsequent experiences from a range of studies at the Leeds Clinical Trials Research Unit (CTRU), a large clinical trials unit in the UK. MAIN TEXT: We implemented a remote eConsent process using the REDCap platform. The process can be used in trials of investigational medicinal products and other intervention types or research designs. Our standard eConsent system focuses on documenting informed consent, with other aspects of consent (e.g. providing information to potential participants and a recruiter discussing the study with each potential participant) occurring outside the system, though trial teams can use electronic methods for these activities where they have ethical approval. Our overall process includes a verbal consent step prior to confidential information being entered onto REDCap and an identity verification step in line with regulator guidance. We considered the regulatory requirements around the system's generation of source documents, how to ensure data protection standards were upheld and how to monitor informed consent within the system. We present four eConsent case studies from the CTRU: two randomised clinical trials and two other health research studies. These illustrate the ways eConsent can be implemented, and lessons learned, including about differences in uptake. CONCLUSIONS: We successfully implemented a remote eConsent process at the CTRU across multiple studies. Our case studies highlight benefits of study participants being able to give consent without having to be present at the study site. This may better align with patient preferences and trial site needs and therefore improve recruitment and resilience against external shocks (such as pandemics). Variation in uptake of eConsent may be influenced more by site-level factors than patient preferences, which may not align well with the aspiration towards patient-centred research. Our current process has some limitations, including the provision of all consent-related text in more than one language, and scalability of implementing more than one consent form version at a time. We consider how enhancements in CTRU processes, or external developments, might affect our approach.