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Abstract 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.

Abstract Objective To investigate whether left atrial (LA) volume and left ventricular filling pressure (LVFP) assessed by cardiovascular magnetic resonance (CMR) change during adenosine delivered myocardial hyperaemia as part of a first-pass stress perfusion study. Methods and results We enrolled 33 patients who had stress CMR. These patients had a baseline four-chamber cine and stress four-chamber cine, which was done at peak myocardial hyperaemic state after administering adenosine. The left and right atria were segmented in the end ventricular diastolic and systolic phases. Short-axis cine stack was segmented for ventricular functional assessment. At peak hyperaemic state, left atrial end ventricular systolic volume just before mitral valve opening increased significantly from baseline in all (91 ± 35ml vs. 81 ± 33ml, P = 0.0002), in males only (99 ± 35ml vs. 88 ± 33ml, P = 0.002) and females only (70 ± 26ml vs. 62 ± 22ml, P = 0.02). The right atrial end ventricular systolic volume increased less significantly from baseline (68 ± 21ml vs. 63 ± 20ml, P = 0.0448). CMR-derived LVFP (equivalent to pulmonary capillary wedge pressure) increased significantly at the peak hyperaemic state in all (15.1 ± 2.9mmHg vs. 14.4 ± 2.8mmHg, P = 0.0002), females only (12.9 ± 2.1mmHg vs. 12.3 ± 1.9mmHg, P = 0.029) and males only (15.9 ± 2.8mmHg vs. 15.2 ± 2.7mmHg, P = 0.002) cohorts. Conclusion Left atrial volume assessment by CMR can measure acute and dynamic changes in preloading conditions on the left ventricle. During adenosine administered first-pass perfusion CMR, left atrial volume and LVFP rise significantly.

Objectives: To study the relationship between serum-free T3 (FT3), C-reactive protein (CRP) and all-cause mortality in patients with acute myocardial infarction (AMI). Design: Prospective multicentre longitudinal cohort study. Methods: Between December 2014 and December 2016, thyroid function and CRP were analysed in AMI (both ST-elevation (STEMI) and non-ST-elevation) patients from the Thyroxine in Acute Myocardial Infarction study. The relationship of FT3 and CRP at baseline with all-cause mortality up to June 2020 was assessed. Mediation analysis was performed to evaluate if CRP mediated the relationship between FT3 and mortality. Results: In 1919 AMI patients (29.2% women, mean (s.d.) age: 64.2 (12.1) years and 48.7% STEMI) followed over a median (interquartile range) period of 51 (46–58) months, there were 277 (14.4%) deaths. Overall, lower serum FT3 and higher CRP levels were associated with higher risk of mortality. When divided the patients into tertiles based on the levels of FT3 and CRP; the group with the lowest FT3 and highest CRP levels had a 2.5-fold increase in mortality risk (adjusted hazard ratio (95% CI) of 2.48 (1.82–3.16)) compared to the group with the highest FT3 and lowest CRP values. CRP mediated 9.8% (95% CI: 6.1–15.0%) of the relationship between FT3 and mortality. Conclusions: In AMI patients, lower serum FT3 levels on admission are associated with a higher mortality risk, which is partly mediated by inflammatio n. Adequately designed trials to explore the potential benefits of T3 in AMI patients a re required.

Background There is a paucity of real-world data assessing the association of operator volumes and mortality specific to primary percutaneous coronary intervention (PPCI).Methods Demographic, clinical and outcome data for all patients undergoing PPCI in Leeds General Infirmary, UK, between 1 January 2009 and 31 December 2011, and 1 January 2013 and 31 December 2013, were obtained prospectively. Operator volumes were analysed according to annual operator PPCI volume (low volume: 1–54 PPCI per year; intermediate volume: 55–109 PPCI per year; high volume: ≥110 PPCI per year). Cox proportional hazards regression analyses were undertaken to investigate 30-day and 12-month all-cause mortality, adjusting for confounding factors.Results During this period, 4056 patients underwent PPCI, 3703 (91.3%) of whom were followed up for a minimum of 12 months. PPCI by low-volume operators was associated with significantly higher adjusted 30-day mortality (HR 1.48 (95% CI 1.05 to 2.08); p=0.02) compared with PPCI performed by high-volume operators, with no significant difference in adjusted 12-month mortality (HR 1.26 (95% CI 0.96 to 1.65); p=0.09). Comparisons between low-volume and intermediate-volume operators, and between intermediate and high-volume operators, showed no significant differences in 30-day and 12-month mortality.Conclusions Low operator volume is independently associated with higher probability of 30-day mortality compared with high operator volume, suggesting a volume–outcome relationship in PPCI at a threshold higher than current recommendations.

Background There are a paucity of randomised data on the optimal timing of invasive coronary angiography (ICA) in higher-risk patients with non-ST elevation myocardial infarction (N-STEMI). International guideline recommendations for early ICA are primarily based on retrospective subgroup analyses of neutral trials.Aims The RAPID N-STEMI trial aims to determine whether very early percutaneous revascularisation improves clinical outcomes as compared with a standard of care strategy in higher-risk N-STEMI patients.Methods and analysis RAPID N-STEMI is a prospective, multicentre, open-label, randomised-controlled, pragmatic strategy trial. Higher-risk N-STEMI patients, as defined by Global Registry of Acute Coronary Events 2.0 score ≥118, or >90 with at least one additional high-risk feature, were randomised to either: very early ICA±revascularisation or standard of care timing of ICA±revascularisation. The primary outcome is the proportion of participants with at least one of the following events (all-cause mortality, non-fatal myocardial infarction and hospital admission for heart failure) at 12 months. Key secondary outcomes include major bleeding and stroke. A hypothesis generating cardiac magnetic resonance (CMR) substudy will provide mechanistic data on infarct size, myocardial salvage and residual ischaemia post percutaneous coronary intervention. On 7 April 2021, the sponsor discontinued enrolment due to the impact of the COVID-19 pandemic and lower than expected event rates. 425 patients were enrolled, and 61 patients underwent CMR.Ethics and dissemination The trial has been reviewed and approved by the East of England Cambridge East Research Ethics Committee (18/EE/0222). The study results will be submitted for publication within 6 months of completion.Trial registration number NCT03707314; Pre-results.

Background: Four-dimensional (4D) flow cardiovascular magnetic resonance imaging (MRI) is an emerging technique used for intra-cardiac blood flow assessment. The role of 4D flow cardiovascular MRI in the assessment of trans-valvular flow in patients with atrial fibrillation (AF) has not previously been assessed. The purpose of this study was to assess the feasibility, image quality, and internal validity of 4D flow cardiovascular MRI in the quantification of trans-valvular flow in patients with AF. Methods: Patients with AF and healthy controls in sinus rhythm underwent cardiovascular MRI, including 4D flow studies. Quality assurance checks were done on the raw data and streamlines. Consistency was investigated by trans-valvular flow assessment between the mitral valve (MV) and the aortic valve (AV). Results: Eight patients with AF (88% male, mean age 62±13 years, mean heart rate (HR) 83±16 beats per minute (bpm)) were included and compared with ten healthy controls (70% male, mean age 41±20 years, mean HR 68.5±9 bpm). All scans were of either good quality with minimal blurring artefacts, or excellent quality with no artefacts. No significant bias was observed between the AV and MV stroke volumes in either healthy controls (–4.8, 95% CI –15.64 to 6.04; P=0.34) or in patients with AF (1.64, 95% CI –4.7 to 7.94; P=0.56). A significant correlation was demonstrated between MV and AV stroke volumes in both healthy controls (r=0.87, 95% CI 0.52 to 0.97; P=0.001) and in AF patients (r=0.82, 95% CI 0.26 to 0.97; P=0.01). Conclusions: In patients with AF, 4D flow cardiovascular MRI is feasible with good image quality, allowing for quantification of trans-valvular flow.

Background: Microvascular obstruction commonly affects patients with acute ST-segment elevation myocardial infarction and is independently associated with adverse outcomes. Objective: To determine whether or not a strategy involving low-dose intracoronary fibrinolytic therapy infused early after coronary reperfusion will reduce microvascular obstruction. Design: This was a multicentre, randomised, double-blind, parallel-group, placebo-controlled, dose-ranging trial. Setting: The trial took place at 11 hospitals in the UK between 17 March 2016 and 21 December 2017. Participants: Patients with acute ST-segment elevation myocardial infarction and a symptom onset to reperfusion time of ≤ 6 hours were eligible for randomisation. Radial artery access was a requirement, and further angiographic criteria included a proximal-to-middle coronary artery occlusion or impaired coronary flow in the presence of a definite thrombus in the culprit coronary artery. Exclusion criteria included a functional coronary collateral supply to the infarct-related artery, any contraindication to fibrinolysis and lack of informed consent. Additional exclusion criteria for safety were (1) requirement for immunosuppressive drug therapy for ≤ 3 months and (2) treatment with an antimicrobial agent. Intervention: A total of 440 participants were randomly assigned 1 : 1 : 1 to treatment with placebo (n = 151), 10 mg of alteplase (n = 144) or 20 mg of alteplase (n = 145) administered by manual infusion directly into the infarct-related coronary artery over 5–10 minutes. The intervention was scheduled to happen after reperfusion and before stent implantation. Outcomes: The primary outcome was the amount of microvascular obstruction (percentage of left ventricular mass) demonstrated by contrast-enhanced cardiac magnetic resonance imaging at 2–7 days after enrolment. The primary analysis was the comparison between the 20 mg of alteplase group and the placebo group; if this comparison was not significant, the comparison of the 10 mg of alteplase group with the placebo group was considered as a secondary analysis. Sample size: A total of 618 patients (minimum of 558 patients). Recruitment was halted on 21 December 2017 given that conditional power for the primary outcome based on a prespecified analysis of the first 267 randomised participants was

Background: Cardiovascular magnetic resonance (CMR) is increasingly used in patients who activate the primary percutaneous coronary intervention (PPCI) pathway to assess heart function. It is uncertain whether having CMR influences patient management or the risk of major adverse cardiovascular events in these patients. Objective: To determine whether or not it is feasible to set up a national registry, linking routinely collected data from hospital information systems (HISs), to investigate the role of CMR in patients who activate the PPCI pathway. Design: A feasibility prospective cohort study. Setting: Four 24/7 PPCI hospitals in England and Wales (two with and two without a dedicated CMR facility). Participants: Patients who activated the PPCI pathway and underwent an emergency coronary angiogram. Interventions: CMR either performed or not performed within 10 weeks of the index event. Main outcome measures: A. Feasibility parameters – (1) patient consent implemented at all hospitals, (2) data extracted from more than one HIS and successfully linked for > 90% of consented patients at all four hospitals, (3) HIS data successfully linked with Hospital Episode Statistics (HES) and Patient Episode Database Wales (PEDW) for > 90% of consented patients at all four hospitals and (4) CMR requested and carried out for ≥ 10% of patients activating the PPCI pathway in CMR hospitals. B. Key drivers of cost-effectiveness for CMR (identified from simple cost-effectiveness models) in patients with (1) multivessel disease and (2) unobstructed coronary arteries. C. A change in clinical management arising from having CMR (defined using formal consensus and identified using HES follow-up data in the 12 months after the index event). Results: A. (1) Consent was implemented (for all hospitals, consent rates were 59–74%) and 1670 participants were recruited. (2) Data submission was variable – clinical data available for ≥ 82% of patients across all hospitals, biochemistry and echocardiography (ECHO) data available for ≥ 98%, 34% and 87% of patients in three hospitals and medications data available for 97% of patients in one hospital. (3) HIS data were linked with hospital episode data for 99% of all consented patients. (4) At the two CMR hospitals, 14% and 20% of patients received CMR. B. In both (1) multivessel disease and (2) unobstructed coronary arteries, the difference in quality-adjusted life-years (QALYs) between CMR and no CMR [‘current’ comparator, stress ECHO and standard ECHO, respectively] was very small [0.0012, 95% confidence interval (CI) –0.0076 to 0.0093 and 0.0005, 95% CI –0.0050 to 0.0077, respectively]. The diagnostic accuracy of the ischaemia tests was the key driver of cost-effectiveness in sensitivity analyses for both patient subgroups. C. There was consensus that CMR leads to clinically important changes in management in five patient subgroups. Some changes in management were successfully identified in hospital episode data (e.g. new diagnoses/procedures, frequency of outpatient episodes related to cardiac events), others were not (e.g. changes in medications, new diagnostic tests). Conclusions: A national registry is not currently feasible. Patients were consented successfully but conventional consent could not be implemented nationally. Linking HIS and hospital episode data was feasible but HIS data were not uniformly available. It is feasible to identify some, but not all, changes in management in the five patient subgroups using hospital episode data. The delay in obtaining hospital episode data influenced the relevance of some of our study objectives. Future work: To test the feasibility of conducting the study using national data sets (e.g. HES, British Cardiovascular Intervention Society audit database, Diagnostic Imaging Dataset, Clinical Practice Research Datalink). Funding: The National Institute for Health Research (NIHR) Health Services and Delivery Research programme. This study was designed and delivered in collaboration with the Clinical Trials and Evaluation Unit, a UK Clinical Research Collaboration-registered clinical trials unit that, as part of the Bristol Trials Centre, is in receipt of NIHR clinical trials unit support funding.

Background: Microvascular obstruction (MVO) predicts short- and longer-term outcomes following primary percutaneous coronary intervention (PPCI) treatment of ST-elevation myocardial infarction (STEMI). The evidence base supporting the role of adenosine and sodium nitroprusside (SNP), the most evaluated adjunctive therapies aimed at attenuating MVO and infarct size, remains weak as the trials involved have had variable end points and used differing drug doses and modes of delivery. Objective: To determine whether intracoronary administration of adenosine or SNP following thrombus aspiration reduces infarct size and/or MVO measured by cardiac magnetic resonance (CMR) imaging in patients undergoing PPCI within 6 hours of onset of STEMI. Design: Multicentre, prospective, parallel, randomised controlled and open-label trial with blinded end point analysis. Setting: Four high-volume UK PPCI centres. Participants: Patients with STEMI undergoing PPCI with Thrombolysis in Myocardial Infarction (TIMI) flow grade 0/1 in the infarct-related artery and no significant bystander coronary artery disease on angiography. Interventions: Participants were anticoagulated with bivalirudin and allocated by an automated 24-hour telephone randomisation service to one of three groups: (1) standard PPCI (control), (2) PPCI with adjunctive adenosine 1–2 mg or (3) PPCI with adjunctive SNP 250 µg. The study drugs were delivered intracoronary immediately following thrombus aspiration and again following successful stenting. Main outcome measures: The primary outcome was infarct size (% total left ventricular end-diastolic mass; %LVM) measured by CMR imaging undertaken 48–96 hours post PPCI. Secondary outcome measures included MVO (hypoenhancement within the infarct core) on CMR imaging, electrocardiographic and angiographic markers of microvascular perfusion and major adverse cardiac events (MACEs) during a median of 6 months’ follow-up. The study aimed to recruit 240 patients (powered at 80% to detect a 5% absolute reduction in infarct size). Results: The trial completed recruitment in April 2014 having randomised 247 patients (standard PPCI group, n = 86; PPCI + adenosine group, n = 82; PPCI + SNP group, n = 79). In total, 79% of participants were male and the mean ± standard deviation age of participants was 59.3 ± 12.3 years. CMR imaging was completed in 197 (80%) patients (standard PPCI, n = 65; PPCI + adenosine, n = 63; PPCI + SNP, n = 69) for the primary outcome. There was no significant difference in infarct size [%LVM, median, interquartile range (IQR)] between the adenosine group (10.1, 4.7–16.2), the SNP group (10.0, 4.2–15.8) and the control group (8.3, 1.9–14.0) (p = 0.062 and p = 0.160 vs. control, respectively). MVO (%LVM, median, IQR) was similar across the groups [1.0, 0.0–3.7 (p = 0.205) and 0.6, 0.0–2.4 (p = 0.244) for adenosine and SNP, respectively, vs. 0.3, 0.0–2.8 for the control]. Using per-protocol analysis, infarct size (%LVM) was increased in adenosine-treated patients compared with control patients (12.0 vs. 8.3; p = 0.031). Increased left ventricular volume and reduced left ventricular ejection fraction were also observed in the adenosine arm. There was a significant increase in MACEs in patients undergoing adenosine-facilitated PPCI compared with control patients, driven by heart failure, at 30 days [hazard ratio (HR) 5.39, 95% confidence interval (CI) 1.18 to 24.60; p = 0.04] and 6 months (HR 6.53, 95% CI 1.46 to 29.2; p = 0.01) post randomisation. Conclusions: High-dose intracoronary adenosine and SNP during PPCI did not reduce infarct size or MVO measured by CMR imaging. Furthermore, adenosine may adversely affect mid-term clinical outcome and should not be used during PPCI to prevent reperfusion injury. Trial registration: ClinicalTrials.gov NCT01747174 and EudraCT 2010–023211–34. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and NIHR partnership.

Background: Complete revascularisation in patients with multivessel disease who are treated with primary percutaneous coronary intervention (PPCI) may improve outcomes compared with an infarct-related artery (IRA)-only strategy. However, non-IRA percutaneous coronary intervention (PCI) may result in additional myocardial infarction (MI). Objectives: To determine whether or not in-hospital complete revascularisation was associated with increased total infarct size (IS) in patients participating in the Complete versus Lesion-only PPCI trial (CvLPRIT). Secondary objectives were to assess whether or not myocardial salvage index, myocardial ischaemia and final IS at follow-up were different with a complete revascularisation versus an IRA-only strategy. Design: Multicentre, prospective, randomised, controlled and open-label trial with blinded end-point analysis. Setting: Seven PPCI centres in England, UK. Participants: ST-segment elevation MI (STEMI) patients with multivessel disease (angiographic stenosis > 70% in one view or > 50% in orthogonal views) presenting within 12 hours of symptom onset and treated with the PPCI. Coronary artery bypass surgery, cardiogenic shock and contraindications to cardiovascular magnetic resonance (CMR; substudy only) imaging were exclusions. Interventions: Patients were randomised to either complete in-hospital revascularisation or an IRA-only strategy. Main outcome measures: The primary outcome was IS as measured by CMR undertaken at 48–72 hours post PPCI. Secondary outcome measures included microvascular obstruction, myocardial salvage index, left ventricular volumes and ejection fraction and final IS on the acute and follow-up CMR carried out at 9 months post STEMI. Results: Patients were recruited from May 2011 until May 2013 and followed up for 12 months. Of 296 patients randomised in the main CvLPRIT, 205 consented to participate in the CMR substudy and 203 had analysable images for the primary end point. Patients in the IRA-only group (n = 105) were well matched to those in the complete revascularisation group (n = 98) for all baseline characteristics {mean age 64.1 years [standard deviation (SD) 10.8 years] vs. 63.1 years (SD 11.3 years); male sex 89% vs. 79%, respectively}. Total IS was not significantly different in the IRA-only and complete revascularisation groups {median 13.5% [interquartile range (IQR) 6.2–21.9%] of left ventricular (LV) mass vs. median 12.6% (IQR 7.2–22.6%) LV mass, respectively; 95% confidence interval –4.09% to 31.17%; p = 0.57}. Myocardial salvage index was also not significantly different in the IRA-only and complete revascularisation groups [median 58.5% (IQR 32.8–74.9%) vs. median 60.5% (IQR 40.6–81.9%), respectively; p = 0.14]. The prevalence of non-IRA MI on acute CMR was higher in the complete revascularisation group than in the IRA-only group (22/98 vs. 11/105, respectively; p = 0.02). There was no difference in total IS, ischaemic burden or LV volumes between treatment groups at follow-up CMR. Limitations: The CMR substudy population may not be a true representation of the overall study population. The optimal timing of CMR to measure IS post PPCI is uncertain. Myocardial salvage was assessable in only 70% of patients. Conclusions: Multivessel PCI, compared with an IRA-only revascularisation, in the setting of STEMI led to a small increase in CMR imaging-detected non-IRA MI, but total IS was not increased. Future work: Larger studies are required to (1) confirm that death and MI are reduced by a complete revascularisation strategy; (2) assess whether or not functional assessment of non-IRA lesions results in similar outcomes to a pragmatic angiographic-based revascularisation strategy; and (3) assess the timing of in-hospital versus staged outpatient complete revascularisation. Trial registration: Current Controlled Trials ISRCTN70913605. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research (NIHR) partnership. The main CvLPRIT was funded by the British Heart Foundation (SP/10/001) with support from the NIHR Comprehensive Local Research Networks.

Abstract Very short duration of dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) has recently attracted a lot of attention with the introduction of newer generations stents. This is appealing, especially in patients at high bleeding risk. However, none of the trials were powered for the individual ischemic and bleeding endpoints. All randomised controlled trials (RCTs) investigating one-month versus routine duration of DAPT in patients undergoing PCI and reporting outcomes from the time of cessation of DAPT (1 month) to 1 year were eligible for inclusion in the meta-analysis. The pooled risk ratios (RR) with their 95% confidence interval (CI) were calculated with the random-effects model using the Mantel-Haenszel method. Four RCTs involving 26,576 patients were included in this meta-analysis. Cessation of DAPT after 1 month was associated with significantly less major bleeding [RR 0.70, 95%CI (0.51–0.95), P = 0.02, heterogeneity (I2) = 42%]. There was no statistically significant difference in all-cause mortality [RR 0.84 (95%CI 0.69–1.03), P = 0.10, I2 = 0%] and stroke [RR 0.71 (95%CI 0.45–1.13), P = 0.15, I2 = 42%] when compared to routine duration of DAPT. There was also no difference in myocardial infarction (MI) [RR 1.12 (95%CI 0.91–1.39), P = 0.28, I2 = 0%], and definite or probable stent thrombosis [RR 1.49 (95%CI 0.92–2.41), P = 0.11, I2 = 0%] with cessation of DAPT after 1 month. Cessation of DAPT 1 month after PCI was associated with significantly less major bleeding, but there was no difference in the rate of all-cause mortality, stroke, MI and stent thrombosis.

Abstract Persistent abnormalities in microcirculatory function are associated with poor clinical outcomes in patients with circulatory shock. We sought to identify patients with acutely reversible microcirculatory dysfunction using a low-dose topical nitroglycerin solution and handheld videomicroscopy during circulatory shock after cardiac surgery. Forty subjects were enrolled for the study, including 20 preoperative control and 20 post-operative patients with shock. To test whether microcirculatory dysfunction is acutely reversible during shock, the sublingual microcirculation was imaged with incident dark field microscopy before and after the application of 0.1 mL of a 1% nitroglycerin solution (1 mg/mL). Compared to the control group, patients with shock had a higher microcirculation heterogeneity index (MHI 0.33 vs. 0.12, p 1.8 SD from shock baseline. Hemodynamics and vasoactive doses did not change during the 30-min study period. Our findings suggest a topical nitroglycerin challenge with handheld videomicroscopy can safely assess for localized recruitment of the microcirculatory blood flow in patients with circulatory shock and may be a useful test to identify nitroglycerin responsiveness.

Abstract Background Accurate evaluation of valvular pathology is crucial in the timing of surgical intervention. Whilst transthoracic echocardiography is widely available and routinely used in the assessment of valvular heart disease, it is bound by several limitations. Although cardiovascular magnetic resonance (CMR) imaging can overcome many of the challenges encountered by echocardiography, it also has a number of limitations. Main text 4D Flow CMR is a novel technique, which allows time-resolved, 3-dimensional imaging. It enables visualisation and direct quantification of flow and peak velocities of all valves simultaneously in one simple acquisition, without any geometric assumptions. It also has the unique ability to measure advanced haemodynamic parameters such as turbulent kinetic energy, viscous energy loss rate and wall shear stress, which may add further diagnostic and prognostic information. Although 4D Flow CMR acquisition can take 5–10 min, emerging acceleration techniques can significantly reduce scan times, making 4D Flow CMR applicable in contemporary clinical practice. Conclusion 4D Flow CMR is an emerging CMR technique, which has the potential to become the new reference-standard method for the evaluation of valvular lesions. In this review, we describe the clinical applications, advantages and disadvantages of 4D Flow CMR in the assessment of valvular heart disease.

Abstract Background Right atrial (RA) area predicts mortality in patients with pulmonary hypertension, and is recommended by the European Society of Cardiology/European Respiratory Society pulmonary hypertension guidelines. The advent of deep learning may allow more reliable measurement of RA areas to improve clinical assessments. The aim of this study was to automate cardiovascular magnetic resonance (CMR) RA area measurements and evaluate the clinical utility by assessing repeatability, correlation with invasive haemodynamics and prognostic value. Methods A deep learning RA area CMR contouring model was trained in a multicentre cohort of 365 patients with pulmonary hypertension, left ventricular pathology and healthy subjects. Inter-study repeatability (intraclass correlation coefficient (ICC)) and agreement of contours (DICE similarity coefficient (DSC)) were assessed in a prospective cohort (n = 36). Clinical testing and mortality prediction was performed in n = 400 patients that were not used in the training nor prospective cohort, and the correlation of automatic and manual RA measurements with invasive haemodynamics assessed in n = 212/400. Radiologist quality control (QC) was performed in the ASPIRE registry, n = 3795 patients. The primary QC observer evaluated all the segmentations and recorded them as satisfactory, suboptimal or failure. A second QC observer analysed a random subcohort to assess QC agreement (n = 1018). Results All deep learning RA measurements showed higher interstudy repeatability (ICC 0.91 to 0.95) compared to manual RA measurements (1st observer ICC 0.82 to 0.88, 2nd observer ICC 0.88 to 0.91). DSC showed high agreement comparing automatic artificial intelligence and manual CMR readers. Maximal RA area mean and standard deviation (SD) DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 is 92.4 ± 3.5 cm2, 91.2 ± 4.5 cm2 and 93.2 ± 3.2 cm2, respectively. Minimal RA area mean and SD DSC metric for observer 1 vs observer 2, automatic measurements vs observer 1 and automatic measurements vs observer 2 was 89.8 ± 3.9 cm2, 87.0 ± 5.8 cm2 and 91.8 ± 4.8 cm2. Automatic RA area measurements all showed moderate correlation with invasive parameters (r = 0.45 to 0.66), manual (r = 0.36 to 0.57). Maximal RA area could accurately predict elevated mean RA pressure low and high-risk thresholds (area under the receiver operating characteristic curve artificial intelligence = 0.82/0.87 vs manual = 0.78/0.83), and predicted mortality similar to manual measurements, both p

BackgroundDespite current resuscitation strategies, circulatory shock and organ injury after cardiac surgery occur in 25-40% of patients. Goal-directed resuscitation after cardiac surgery has generated significant interest, but clinical practice to normalize hemodynamic variables including mean arterial pressure, cardiac filling pressures, and cardiac output may not reverse microcirculation abnormalities and do not address cellular dysoxia. Recent advances in technology have made it possible to measure critical components of oxygen delivery and oxygen utilization systems in live human tissues and blood cells. The MicroRESUS study will be the first study to measure microcirculatory and mitochondrial function in patients with circulatory shock and link these findings with clinical outcomes.Methods and analysisThis will be a prospective, observational study that includes patients undergoing elective cardiovascular surgery with cardiopulmonary bypass (CPB). Microcirculation will be quantified with sublingual incident dark field videomicroscopy. Mitochondrial respiration will be measured by performing a substrate-uncoupler-inhibitor titration protocol with high resolution respirometry on peripheral blood mononuclear cells at baseline and serial timepoints during resuscitation and at recovery as a possible liquid biomarker. Plasma samples will be preserved for future analysis to examine endothelial injury and other mechanisms of microcirculatory dysfunction. Thirty-day ventilator and vasopressor-free days (VVFDs) will be measured as a primary outcome, along with sequential organ failure assessment scores, and other clinical parameters to determine if changes in microcirculation and mitochondrial respiration are more strongly associated with clinical outcomes compared to traditional resuscitation targets.DiscussionThis will be the first prospective study to examine both microcirculatory and mitochondrial function in human patients with circulatory shock undergoing cardiac bypass and address a key mechanistic knowledge gap in the cardiovascular literature. The results of this study will direct future research efforts and therapeutic development for patients with shock.

Background Impaired microcirculatory reperfusion worsens prognosis following acute ST‐segment–elevation myocardial infarction. In the T‐TIME (A Trial of Low‐Dose Adjunctive Alteplase During Primary PCI) trial, microvascular obstruction on cardiovascular magnetic resonance imaging did not differ with adjunctive, low‐dose, intracoronary alteplase (10 or 20 mg) versus placebo during primary percutaneous coronary intervention. We evaluated the effects of intracoronary alteplase, during primary percutaneous coronary intervention, on the index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio. Methods and Results A prespecified physiology substudy of the T‐TIME trial. From 2016 to 2017, patients with ST‐segment–elevation myocardial infarction ≤6 hours from symptom onset were randomized in a double‐blind study to receive alteplase 20 mg, alteplase 10 mg, or placebo infused into the culprit artery postreperfusion, but prestenting. Index of microcirculatory resistance, coronary flow reserve, and resistive reserve ratio were measured after percutaneous coronary intervention. Cardiovascular magnetic resonance was performed at 2 to 7 days and 3 months. Analyses in relation to ischemic time (

Background Spironolactone may have prognostic benefit in selected patients with heart failure with preserved ejection fraction. This study assessed the myocardial tissue effects of spironolactone in heart failure with preserved ejection fraction. Methods and Results A 1:1 randomized controlled study of 6 months of spironolactone versus control in heart failure with preserved ejection fraction. The primary outcome was change in myocardial extracellular volume fraction by cardiovascular magnetic resonance as a surrogate of diffuse fibrosis. Of 55 randomized patients, 40 (20 women; age, 75.2±5.9 years) completed follow‐up (19 treatment, 21 control). A significant change in extracellular volume over the study period was not seen (treatment, 28.7±3.7% versus 27.7±3.4% [P=0.14]; controls, 27.6±3.4% versus 28.3±4.4% [P=0.14]); however, the rate of extracellular volume expansion was decreased by spironolactone (−1.0±2.4% versus 0.8±2.2%). Indexed left ventricular mass decreased with treatment (104.4±26.6 versus 94.0±20.6 g/m2; P=0.001) but not in controls (101.4±29.4 versus 104.0±32.8 g/m2; P=0.111). Extracellular mass decreased by 13.8% (15.1±4.8 versus 13.0±3.4 g/m2; P=0.003), and cellular mass decreased by 8.3% (37.6±10.0 versus 34.3±7.9 g/m2; P=0.001) with spironolactone, but was static in controls. Conclusions Spironolactone did not lead to significant change in extracellular volume. However, spironolactone did decrease rate of extracellular expansion, with a decrease in the mass of both cellular and extracellular myocardial compartments. These data point to the mechanism of action of spironolactone in heart failure with preserved ejection fraction, including a direct tissue effect with a reduction in rate of myocardial fibrosis.

Abstract Background Non-invasive assessment of myocardial ischaemia is a cornerstone of the diagnosis of coronary artery disease. Measurement of myocardial blood flow (MBF) using positron emission tomography (PET) is the current reference standard for non-invasive quantification of myocardial ischaemia. Dynamic myocardial perfusion cardiovascular magnetic resonance (CMR) offers an alternative to PET and a recently developed method with automated inline perfusion mapping has shown good correlation of MBF values between CMR and PET. This study assessed the repeatability of myocardial perfusion mapping by CMR in healthy subjects. Methods Forty-two healthy subjects were recruited and underwent adenosine stress and rest perfusion CMR on two visits. Scans were repeated with a minimum interval of 7 days. Intrastudy rest and stress MBF repeatability were assessed with a 15-min interval between acquisitions. Interstudy rest and stress MBF and myocardial perfusion reserve (MPR) were measured for global myocardium and regionally for coronary territories and slices. Results There was no significant difference in intrastudy repeated global rest MBF (0.65 ± 0.13 ml/g/min vs 0.62 ± 0.12 ml/g/min, p = 0.24, repeatability coefficient (RC) =24%) or stress (2.89 ± 0.56 ml/g/min vs 2.83 ± 0.64 ml/g/min, p = 0.41, RC = 29%) MBF. No significant difference was seen in interstudy repeatability for global rest MBF (0.64 ± 0.13 ml/g/min vs 0.64 ± 0.15 ml/g/min, p = 0.80, RC = 32%), stress MBF (2.71 ± 0.61 ml/g/min vs 2.55 ± 0.57 ml/g/min, p = 0.12, RC = 33%) or MPR (4.24 ± 0.69 vs 3.73 ± 0.76, p = 0.25, RC = 36%). Regional repeatability was good for stress (RC = 30–37%) and rest MBF (RC = 32–36%) but poorer for MPR (RC = 35–43%). Within subject coefficient of variation was 8% for rest and 11% for stress within the same study, and 11% for rest and 12% for stress between studies. Conclusions Fully automated, inline, myocardial perfusion mapping by CMR shows good repeatability that is similar to the published PET literature. Both rest and stress MBF show better repeatability than MPR, particularly in regional analysis.

Abstract Background We aimed to investigate in patients with type 2 diabetes whether aortic stiffness is: (i) associated with glycaemic control, (ii) associated with adverse outcomes and (iii) can be reversed on treatment with RAAS inhibition. Methods Patients with type 2 diabetes (N = 94) and low vascular risk underwent assessment of cardiovascular risk and CMR assessment of ascending aortic distensibility (AAD), descending aortic distensibility (DAD) and aortic pulse wave velocity (PWV). Of these patients a subgroup with recent onset microalbuminuria (N = 25) were treated with renin–angiotensin–aldosterone system (RAAS) inhibition and imaging repeated after 1 year. All 94 patients were followed up for 2.4 years for major adverse cardiovascular disease (CVD) events including myocardial infarction detected on late gadolinium enhancement CMR. Results Ascending aortic distensibility, DAD and PWV all had a significant association with age and 24 h systolic blood pressure but only AAD had a significant association with glycaemic control, measured as HbA1c (Beta − 0.016, P = 0.04). The association between HbA1c and AAD persisted even after correction for age and hypertension. CVD events occurred in 19/94 patients. AAD, but not DAD or PWV, was associated with CVD events (hazard ratio 0.49, 95% confidence interval 0.25–0.95, P = 0.01). On treatment with RAAS inhibition, AAD, but not DAD or PWV, showed significant improvement from 1.51 ± 1.15 to 1.97 ± 1.07 10−3 mmHg−1, P = 0.007. Conclusions Ascending aortic distensibility measured by CMR is independently associated with poor glycaemic control and adverse cardiovascular events. Furthermore it may be reversible on treatment with RAAS inhibition. AAD is a promising marker of cardiovascular risk in asymptomatic patients with type 2 diabetes and has potential use as a surrogate cardiovascular endpoint in studies of novel hypoglycaemic agents. Clinical trials registration https://clinicaltrials.gov/ct2/show/NCT01970319

BackgroundPatients with type 2 diabetes mellitus and elevated urinary albumin:creatinine ratio (ACR) have increased risk of heart failure. We hypothesized this was because of cardiac tissue changes rather than silent coronary artery disease. Methods and ResultsIn a case‐controlled observational study 130 subjects including 50 ACR+ve diabetes mellitus patients with persistent microalbuminuria (ACR >2.5 mg/mol in males and >3.5 mg/mol in females, ≥2 measurements, no previous renin–angiotensin–aldosterone therapy, 50 ACR−ve diabetes mellitus patients and 30 controls underwent cardiovascular magnetic resonance for investigation of myocardial fibrosis, ischemia and infarction, and echocardiography. Thirty ACR+ve patients underwent further testing after 1‐year treatment with renin–angiotensin–aldosterone blockade. Cardiac extracellular volume fraction, a measure of diffuse fibrosis, was higher in diabetes mellitus patients than controls (26.1±3.4% and 23.3±3.0% P=0.0002) and in ACR+ve than ACR−ve diabetes mellitus patients (27.2±4.1% versus 25.1±2.9%, P=0.004). ACR+ve patients also had lower E′ measured by echocardiography (8.2±1.9 cm/s versus 8.9±1.9 cm/s, P=0.04) and elevated high‐sensitivity cardiac troponin T 18% versus 4% ≥14 ng/L (P=0.05). Rate of silent myocardial ischemia or infarction were not influenced by ACR status. Renin–angiotensin–aldosterone blockade was associated with increased left ventricular ejection fraction (59.3±7.8 to 61.5±8.7%, P=0.03) and decreased extracellular volume fraction (26.5±3.6 to 25.2±3.1, P=0.01) but no changes in diastolic function or high‐sensitivity cardiac troponin T levels. ConclusionsAsymptomatic diabetes mellitus patients with persistent microalbuminuria have markers of diffuse cardiac fibrosis including elevated extracellular volume fraction, high‐sensitivity cardiac troponin T, and diastolic dysfunction, which may in part be reversible by renin–angiotensin–aldosterone blockade. Increased risk in these patients may be mediated by subclinical changes in tissue structure and function. Clinical Trial RegistrationURL: https://www.clinicaltrials.gov. Unique identifier: NCT01970319.