Fractional Flow Reserve and Instantaneous Wave-Free Ratio as Predictors of the Placebo-Controlled Response to Percutaneous Coronary Intervention in Stable Coronary Artery Disease.

BACKGROUND: The Placebo-controlled Trial of Percutaneous Coronary Intervention for the Relief of Stable Angina (ORBITA-2) provided evidence for the role of percutaneous coronary intervention (PCI) for angina relief in stable coronary artery disease (CAD). Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are often used to guide PCI, however their ability to predict placebo-controlled angina improvement is unknown. METHODS: Participants with angina, ischemia, and stable CAD were enrolled and antianginal medications were stopped. Participants reported angina episodes daily for 2 weeks using the ORBITA-app. At the research angiogram, FFR and iFR were measured. After sedation and auditory isolation, participants were randomized to PCI or placebo, before entering a 12-week blinded follow-up phase with daily angina reporting. The ability of FFR and iFR, analyzed as continuous variables, to predict the placebo-controlled effect of PCI, was tested using Bayesian proportional odds modelling. RESULTS: Invasive physiology data were available in 279 patients (140 PCI and 139 placebo). The median (IQR) age was 65 years (59.0 to 70.5) and 223 (79.9%) were male. Median FFR was 0.60 (0.46 to 0.73) and median iFR was 0.76 (0.50 to 0.86). The lower the FFR or iFR, the greater the placebo-controlled improvement with PCI across all endpoints. There was strong evidence that a patient with an FFR at the lower quartile would have a greater placebo-controlled improvement in angina symptom score with PCI than a patient at the upper quartile (FFR 0.46 vs. 0.73: OR 2.01, 95% CrI 1.79 to 2.26, Pr(Interaction)>99.9%). Similarly, there was strong evidence that a patient with an iFR at the lower quartile would have a greater placebo controlled improvement in angina symptom score with PCI than a patient with an iFR at the upper quartile (iFR 0.50 vs. 0.86: OR 2.13, 95% CrI 1.87 to 2.45, Pr(Interaction) >99.9%). The relationship between benefit and physiology was seen in both Rose angina and Rose nonangina. CONCLUSIONS: Physiological stenosis severity, as measured by FFR and iFR, predicts placebo-controlled angina relief from PCI. Invasive coronary physiology can be used to target PCI to those patients who are most likely to experience benefit.

Comparison of acute hemodynamic effect of prioritizing ventricular resynchronization vs left ventricular filling during optimization of cardiac resynchronization therapy.

BACKGROUND: Targeting maximal ventricular resynchronization, with the shortest QRS duration (QRSd), is commonly implemented after cardiac resynchronization therapy (CRT). OBJECTIVE: The purpose of this study was to compare optimization of ventricular resynchronization with optimization of left ventricular (LV) filling during CRT by measuring their acute hemodynamic effects. METHODS: Patients with standard CRT indications, recruited from 2 centers, underwent biventricular pacing (BVP) and left bundle branch pacing (LBBP). We performed a within-patient comparison of acute hemodynamic response of systolic blood pressure (SBP) at the atrioventricular delay (AVD) with the shortest QRSd against the AVD with the most efficient LV filling. In a validation substudy, we also performed electrical assessment using QRS area (QRSa) and hemodynamic assessment with the maximum rate of LV pressure rise (dP/dtmax). RESULTS: Thirty patients (age 65 ± 10 years; 53% male) were recruited. The AVD producing maximal ventricular resynchronization was associated with a significantly shorter QRSd (difference 15 ± 12 ms for BVP and 18 ± 13 ms for LBBP, both P <.01) and a significantly smaller improvement in SBP (difference -3 ± 4 mm Hg for BVP and -2 ± 2 mm Hg for LBBP, both P <.01) compared with the AVD that optimized filling. Similar findings were observed in the substudy, with a significantly smaller improvement in dP/dtmax assessed with QRSd and QRSa (difference -9% ± 7% and -6% ± 4% during BVP, and -5% ± 6% and -3% ± 3% during LBBP, all P <.01). CONCLUSION: Targeting the maximal ventricular resynchronization results in suboptimal acute hemodynamic performance with both BVP and LBBP as CRT. These findings support prioritizing LV filling when programming AVD for CRT.

The arrhythmic substrate of hypertrophic cardiomyopathy using ECG imaging.

Introduction: Patients with hypertrophic cardiomyopathy (HCM) are at risk for lethal ventricular arrhythmia, but the electrophysiological substrate behind this is not well-understood. We used non-invasive electrocardiographic imaging to characterize patients with HCM, including cardiac arrest survivors. Methods: HCM patients surviving ventricular fibrillation or hemodynamically unstable ventricular tachycardia (n = 17) were compared to HCM patients without a personal history of potentially lethal arrhythmia (n = 20) and a pooled control group with structurally normal hearts. Subjects underwent exercise testing by non-invasive electrocardiographic imaging to estimate epicardial electrophysiology. Results: Visual inspection of reconstructed epicardial HCM maps revealed isolated patches of late activation time (AT), prolonged activation-recovery intervals (ARIs), as well as reversal of apico-basal trends in T-wave inversion and ARI compared to controls (p < 0.005 for all). AT and ARI were compared between groups. The pooled HCM group had longer mean AT (60.1 ms vs. 52.2 ms, p < 0.001), activation dispersion (55.2 ms vs. 48.6 ms, p = 0.026), and mean ARI (227 ms vs. 217 ms, p = 0.016) than structurally normal heart controls. HCM ventricular arrhythmia survivors could be differentiated from HCM patients without a personal history of life-threatening arrhythmia by longer mean AT (63.2 ms vs. 57.4 ms, p = 0.007), steeper activation gradients (0.45 ms/mm vs. 0.36 ms/mm, p = 0.011), and longer mean ARI (234.0 ms vs. 221.4 ms, p = 0.026). A logistic regression model including whole heart mean activation time and activation recovery interval could identify ventricular arrhythmia survivors from the HCM cohort, producing a C statistic of 0.76 (95% confidence interval 0.72-0.81), with an optimal sensitivity of 78.6% and a specificity of 79.8%. Discussion: The HCM epicardial electrotype is characterized by delayed, dispersed conduction and prolonged, dispersed activation-recovery intervals. Combination of electrophysiologic measures with logistic regression can improve differentiation over single variables. Future studies could test such models prospectively for risk stratification of sudden death due to HCM.

Automating quality control in cardiac magnetic resonance: Artificial intelligence for discriminative assessment of planning and motion artifacts and real-time reacquisition guidance.

BACKGROUND: Accurate measurements from cardiovascular magnetic resonance (CMR) images require precise positioning of scan planes and elimination of motion artifacts from arrhythmia or breathing. Unidentified or incorrectly managed artifacts degrade image quality, invalidate clinical measurements, and decrease diagnostic confidence. Currently, radiographers must manually inspect each acquired image to confirm diagnostic quality and decide whether reacquisition or a change in sequences is warranted. We aimed to develop artificial intelligence (AI) to provide continuous quality scores across different quality domains, and from these, determine whether cines are clinically adequate, require replanning, or warrant a change in protocol. METHODS: A three-dimensional convolutional neural network was trained to predict cine quality graded on a continuous scale by a level 3 CMR expert, focusing separately on planning and motion artifacts. It incorporated four distinct output heads for the assessment of image quality in terms of (a, b, c) 2-, 3- and 4-chamber misplanning, and (d) long- and short-axis arrhythmia/breathing artifact. Backpropagation was selectively performed across these heads based on the labels present for each cine. Each image in the testing set was reported by four level 3 CMR experts, providing a consensus on clinical adequacy. The AI's assessment of image quality and ability to identify images requiring replanning or sequence changes were evaluated with Spearman's rho and the area under receiver operating characteristic curve (AUROC), respectively. RESULTS: A total of 1940 cines across 1387 studies were included. On the test set of 383 cines, AI-judged image quality correlated strongly with expert judgment, with Spearman's rho of 0.84, 0.84, 0.81, and 0.81 for 2-, 3- and 4-chamber planning quality and the extent of arrhythmia or breathing artifacts, respectively. The AI also showed high efficacy in flagging clinically inadequate cines (AUROC 0.88, 0.93, and 0.93 for identifying misplanning of 2-, 3- and 4-chamber cines, and 0.90 for identifying movement artifacts). CONCLUSION: AI can assess distinct domains of CMR cine quality and provide continuous quality scores that correlate closely with a consensus of experts. These ratings could be used to identify cases where reacquisition is warranted and guide corrective actions to optimize image quality, including replanning, prospective gating, or real-time imaging.

Predictors of the efficacy of His bundle pacing in patients with a prolonged PR interval: A stratified analysis of the HOPE-HF randomized controlled trial.

AIMS: The randomized, double-blind, placebo-controlled HOPE-HF trial assessed the benefit of atrio-ventricular (AV) delay optimization delivered using His bundle pacing. It recruited patients with left ventricular ejection fraction ≤40%, PR interval ≥200 ms, and baseline QRS ≤140 ms or right bundle branch block. Overall, there was no significant increase in peak oxygen uptake (VO2max) but there was significant improvement in heart failure specific quality of life. In this pre-specified secondary analysis, we evaluated the impact of baseline PR interval, echocardiographic E-A fusion, and the magnitude of acute high-precision haemodynamic response to pacing, on outcomes. METHODS AND RESULTS: All 167 randomized participants underwent measurement of PR interval, acute haemodynamic response at optimized AV delay, and assessment of presence of E-A fusion. We tested the impact of these baseline parameters using a Bayesian ordinal model on VO2max, quality of life and activity measures. There was strong evidence of a beneficial interaction between the baseline acute haemodynamic response and the blinded benefit of pacing for VO2 (Pr 99.9%), Minnesota Living With Heart Failure (MLWHF) (Pr 99.8%), MLWHF physical limitation score (Pr 98.9%), EQ-5D visual analogue scale (Pr 99.6%), and exercise time (Pr 99.4%). The baseline PR interval and the presence of baseline E-A fusion did not have this reliable ability to predict the clinical benefit of pacing over placebo across multiple endpoints. CONCLUSIONS: In the HOPE-HF trial, the acute haemodynamic response to pacing reliably identified patients who obtained clinical benefit. Patients with a long PR interval (≥200 ms) and left ventricular impairment who obtained acute haemodynamic improvement with AV-optimized His bundle pacing were likely to obtain clinical benefit, consistent across multiple endpoints. Importantly, this gradation can be reliably tested for before randomization, but does require high-precision AV-optimized haemodynamic assessment to be performed.

2-Dimensional Echocardiographic Global Longitudinal Strain With Artificial Intelligence Using Open Data From a UK-Wide Collaborative.

BACKGROUND: Global longitudinal strain (GLS) is reported to be more reproducible and prognostic than ejection fraction. Automated, transparent methods may increase trust and uptake. OBJECTIVES: The authors developed open machine-learning-based GLS methodology and validate it using multiexpert consensus from the Unity UK Echocardiography AI Collaborative. METHODS: We trained a multi-image neural network (Unity-GLS) to identify annulus, apex, and endocardial curve on 6,819 apical 4-, 2-, and 3-chamber images. The external validation dataset comprised those 3 views from 100 echocardiograms. End-systolic and -diastolic frames were each labelled by 11 experts to form consensus tracings and points. They also ordered the echocardiograms by visual grading of longitudinal function. One expert calculated global strain using 2 proprietary packages. RESULTS: The median GLS, averaged across the 11 individual experts, was -16.1 (IQR: -19.3 to -12.5). Using each case's expert consensus measurement as the reference standard, individual expert measurements had a median absolute error of 2.00 GLS units. In comparison, the errors of the machine methods were: Unity-GLS 1.3, proprietary A 2.5, proprietary B 2.2. The correlations with the expert consensus values were for individual experts 0.85, Unity-GLS 0.91, proprietary A 0.73, proprietary B 0.79. Using the multiexpert visual ranking as the reference, individual expert strain measurements found a median rank correlation of 0.72, Unity-GLS 0.77, proprietary A 0.70, and proprietary B 0.74. CONCLUSIONS: Our open-source approach to calculating GLS agrees with experts' consensus as strongly as the individual expert measurements and proprietary machine solutions. The training data, code, and trained networks are freely available online.

The assessment of left ventricular diastolic function: guidance and recommendations from the British Society of Echocardiography.

Impairment of left ventricular (LV) diastolic function is common amongst those with left heart disease and is associated with significant morbidity. Given that, in simple terms, the ventricle can only eject the volume with which it fills and that approximately one half of hospitalisations for heart failure (HF) are in those with normal/'preserved' left ventricular ejection fraction (HFpEF) (Bianco et al. in JACC Cardiovasc Imaging. 13:258-271, 2020. 10.1016/j.jcmg.2018.12.035), where abnormalities of ventricular filling are the cause of symptoms, it is clear that the assessment of left ventricular diastolic function (LVDF) is crucial for understanding global cardiac function and for identifying the wider effects of disease processes. Invasive methods of measuring LV relaxation and filling pressures are considered the gold-standard for investigating diastolic function. However, the high temporal resolution of trans-thoracic echocardiography (TTE) with widely validated and reproducible measures available at the patient's bedside and without the need for invasive procedures involving ionising radiation have established echocardiography as the primary imaging modality. The comprehensive assessment of LVDF is therefore a fundamental element of the standard TTE (Robinson et al. in Echo Res Pract7:G59-G93, 2020. 10.1530/ERP-20-0026). However, the echocardiographic assessment of diastolic function is complex. In the broadest and most basic terms, ventricular diastole comprises an early filling phase when blood is drawn, by suction, into the ventricle as it rapidly recoils and lengthens following the preceding systolic contraction and shortening. This is followed in late diastole by distension of the compliant LV when atrial contraction actively contributes to ventricular filling. When LVDF is normal, ventricular filling is achieved at low pressure both at rest and during exertion. However, this basic description merely summarises the complex physiology that enables the diastolic process and defines it according to the mechanical method by which the ventricles fill, overlooking the myocardial function, properties of chamber compliance and pressure differentials that determine the capacity for LV filling. Unlike ventricular systolic function where single parameters are utilised to define myocardial performance (LV ejection fraction (LVEF) and Global Longitudinal Strain (GLS)), the assessment of diastolic function relies on the interpretation of multiple myocardial and blood-flow velocity parameters, along with left atrial (LA) size and function, in order to diagnose the presence and degree of impairment. The echocardiographic assessment of diastolic function is therefore multifaceted and complex, requiring an algorithmic approach that incorporates parameters of myocardial relaxation/recoil, chamber compliance and function under variable loading conditions and the intra-cavity pressures under which these processes occur. This guideline outlines a structured approach to the assessment of diastolic function and includes recommendations for the assessment of LV relaxation and filling pressures. Non-routine echocardiographic measures are described alongside guidance for application in specific circumstances. Provocative methods for revealing increased filling pressure on exertion are described and novel and emerging modalities considered. For rapid access to the core recommendations of the diastolic guideline, a quick-reference guide (additional file 1) accompanies the main guideline document. This describes in very brief detail the diastolic investigation in each patient group and includes all algorithms and core reference tables.

Therapeutic options for neurocardiogenic syncope: a meta-analysis of randomised trials with and without blinding.

BACKGROUND: Neurocardiogenic syncope is a common condition with significant associated psychological and physical morbidity. The effectiveness of therapeutic options for neurocardiogenic syncope beyond placebo remains uncertain. METHODS: The primary endpoint was the risk ratio (RR) of spontaneously recurring syncope following any therapeutic intervention. We also examined the effect of blinding on treatment efficacy. We identified all randomised trials which evaluated the effect of any pharmacological, device-based or supportive intervention on patients with a history of syncope. A systematic search was conducted on Medline, Embase, PubMed databases and Cochrane Central Register for Controlled Trials from 1950 to 25 April 2023. Event rates, their RRs and 95% CIs were calculated, and a random-effects meta-analysis was conducted for each intervention. Data analysis was performed in R using RStudio. RESULTS: We identified 47 eligible trials randomising 3518 patients. Blinded trials assessing syncope recurrence were neutral for beta blockers, fludrocortisone and conventional dual-chamber pacing but were favourable for selective serotonin reuptake inhibitors (SSRIs) (RR 0.40, 95% CI 0.26 to 0.63, p<0.001), midodrine (RR 0.70, 95% CI 0.53 to 0.94, p=0.016) and closed-loop stimulation (CLS) pacing (RR 0.15, 95% CI 0.07 to 0.35, p<0.001). Unblinded trials reported significant benefits for all therapy categories other than beta blockers and consistently showed larger benefits than blinded trials. CONCLUSIONS: Under blinded conditions, SSRIs, midodrine and CLS pacing significantly reduced syncope recurrence. Future trials for syncope should be blinded to avoid overestimating treatment effects. PROSPERO REGISTRATION NUMBER: CRD42022330148.

N-of-1 Trial of Angina Verification Before Percutaneous Coronary Intervention.

BACKGROUND: In stable coronary artery disease, 30% to 60% of patients remain symptomatic despite successful revascularization. Perhaps not all symptoms reported by a patient with myocardial ischemia are, in fact, angina. OBJECTIVES: This study sought to determine whether independent symptom verification using a placebo-controlled ischemic stimulus could distinguish which patients achieve greatest symptom relief from percutaneous coronary intervention (PCI). METHODS: ORBITA-STAR was a multicenter, n-of-1, placebo-controlled study in patients undergoing single-vessel PCI for stable symptoms. Participants underwent 4 episodes (60 seconds each) of low-pressure balloon occlusion across their coronary stenosis, randomly paired with 4 episodes of placebo inflation. Following each episode, patients reported the similarity of the induced symptom in comparison with their usual symptom. The similarity score ranged from -10 (placebo replicated the symptom more than balloon occlusion) to +10 (balloon occlusion exactly replicated the symptom). The primary endpoint was the ability of the similarity score to predict symptom relief with PCI. RESULTS: Fifty-one patients were recruited, aged 62.9 ± 8.6 years. The median fractional flow reserve was 0.68 (Q1-Q3: 0.57-0.79), and the instantaneous wave-free ratio was 0.80 (Q1-Q3: 0.48-0.89). The median similarity score was 3 (Q1-Q3: 0.875-5.25). The similarity score was a strong predictor of symptom improvement following PCI: a patient with an upper quartile similarity score of 5.25 was significantly more likely to have lower angina frequency at follow-up (OR: 8.01; 95% credible interval: 2.39-15.86) than a patient with a lower quartile similarity score of 0.875 (OR: 1.31; 95% credible interval: 0.71-1.99), Pr(difference) >99.9%. CONCLUSIONS: Similarity score powerfully predicted symptom improvement from PCI. These data lay the foundation for independent symptom mapping to target PCI to those patients most likely to benefit. (Systematic Trial of Angina Assessment Before Revascularization [ORBITA-STAR]; NCT04280575).

Symptoms as a Predictor of the Placebo-Controlled Efficacy of PCI in Stable Coronary Artery Disease.

BACKGROUND: Placebo-controlled evidence from ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) found that percutaneous coronary intervention (PCI) in stable coronary artery disease with little or no antianginal medication relieved angina, but residual symptoms persisted in many patients. The reason for this was unclear. OBJECTIVES: This ORBITA-2 secondary analysis investigates the relationship between presenting symptoms and disease severity (anatomic, noninvasive, and invasive ischemia) and the ability of symptoms to predict the placebo-controlled efficacy of PCI. METHODS: Prerandomization symptom severity and nature were assessed using the ORBITA smartphone application and symptom and quality of life questionnaires including the World Health Organization Rose angina questionnaire (Rose). Disease severity was assessed using quantitative coronary angiography, stress echocardiography, fractional flow reserve, and instantaneous wave-free ratio. Bayesian ordinal regression was used. RESULTS: At prerandomization, the median number of daily angina episodes was 0.8 (Q1-Q3: 0.4-1.6), 64% had Rose angina, quantitative coronary angiography diameter stenosis was 61% (Q1-Q3: 49%-74%), stress echocardiography score was 1.0 (Q1-Q3: 0.0-2.7), fractional flow reserve was 0.63 (Q1-Q3: 0.49-0.75), and instantaneous wave-free ratio was 0.78 (Q1-Q3: 0.55-0.87). There was little relationship between symptom severity and nature and disease severity: angina symptom score with quantitative coronary angiography ordinal correlation coefficient: 0.06 (95% credible interval [CrI]: 0.00-0.08); stress echocardiography: 0.09 (95% CrI: 0.02-0.10); fractional flow reserve: 0.04 (95% CrI: -0.03 to 0.07); and instantaneous wave-free ratio: 0.04 (95% CrI: -0.01 to 0.07). However, Rose angina and guideline-based typical angina were strong predictors of placebo-controlled PCI efficacy (angina symptom score: OR: 1.9; 95% CrI: 1.6-2.1; probability of interaction [PrInteraction] = 99.9%; and OR: 1.8; 95% CrI: 1.6-2.1; PrInteraction = 99.9%, respectively). CONCLUSIONS: Although symptom severity and nature were poorly associated with disease severity, the nature of symptoms powerfully predicted the placebo-controlled efficacy of PCI.

Coronary sinus reducer for the treatment of refractory angina (ORBITA-COSMIC): a randomised, placebo-controlled trial.

BACKGROUND: The coronary sinus reducer (CSR) is proposed to reduce angina in patients with stable coronary artery disease by improving myocardial perfusion. We aimed to measure its efficacy, compared with placebo, on myocardial ischaemia reduction and symptom improvement. METHODS: ORBITA-COSMIC was a double-blind, randomised, placebo-controlled trial conducted at six UK hospitals. Patients aged 18 years or older with angina, stable coronary artery disease, ischaemia, and no further options for treatment were eligible. All patients completed a quantitative adenosine-stress perfusion cardiac magnetic resonance scan, symptom and quality-of-life questionnaires, and a treadmill exercise test before entering a 2-week symptom assessment phase, in which patients reported their angina symptoms using a smartphone application (ORBITA-app). Patients were randomly assigned (1:1) to receive either CSR or placebo. Both participants and investigators were masked to study assignment. After the CSR implantation or placebo procedure, patients entered a 6-month blinded follow-up phase in which they reported their daily symptoms in the ORBITA-app. At 6 months, all assessments were repeated. The primary outcome was myocardial blood flow in segments designated ischaemic at enrolment during the adenosine-stress perfusion cardiac magnetic resonance scan. The primary symptom outcome was the number of daily angina episodes. Analysis was done by intention-to-treat and followed Bayesian methodology. The study is registered with ClinicalTrials.gov, NCT04892537, and completed. FINDINGS: Between May 26, 2021, and June 28, 2023, 61 patients were enrolled, of whom 51 (44 [86%] male; seven [14%] female) were randomly assigned to either the CSR group (n=25) or the placebo group (n=26). Of these, 50 patients were included in the intention-to-treat analysis (24 in the CSR group and 26 in the placebo group). 454 (57%) of 800 imaged cardiac segments were ischaemic at enrolment, with a median stress myocardial blood flow of 1·08 mL/min per g (IQR 0·77-1·41). Myocardial blood flow in ischaemic segments did not improve with CSR compared with placebo (difference 0·06 mL/min per g [95% CrI -0·09 to 0·20]; Pr(Benefit)=78·8%). The number of daily angina episodes was reduced with CSR compared with placebo (OR 1·40 [95% CrI 1·08 to 1·83]; Pr(Benefit)=99·4%). There were two CSR embolisation events in the CSR group, and no acute coronary syndrome events or deaths in either group. INTERPRETATION: ORBITA-COSMIC found no evidence that the CSR improved transmural myocardial perfusion, but the CSR did improve angina compared with placebo. These findings provide evidence for the use of CSR as a further antianginal option for patients with stable coronary artery disease. FUNDING: Medical Research Council, Imperial College Healthcare Charity, National Institute for Health and Care Research Imperial Biomedical Research Centre, St Mary's Coronary Flow Trust, British Heart Foundation.

Placebo Control and Blinding in Randomized Trials of Procedural Interventions: A Systematic Review and Meta-Regression.

Importance: Unlike medications, procedural interventions are rarely trialed against placebo prior to becoming accepted in clinical practice. When placebo-controlled trials are eventually conducted, procedural interventions may be less effective than previously believed. Objective: To investigate the importance of including a placebo arm in trials of surgical and interventional procedures by comparing effect sizes from trials of the same procedure that do and do not include a placebo arm. Data Sources: Searches of MEDLINE and Embase identified all placebo-controlled trials for procedural interventions in any specialty of medicine and surgery from inception to March 31, 2019. A secondary search identified randomized clinical trials assessing the same intervention, condition, and end point but without a placebo arm for paired comparison. Study Selection: Placebo-controlled trials of anatomically site-specific procedures requiring skin incision or endoscopic techniques were eligible for inclusion; these were then matched to trials without placebo control that fell within prespecified limits of heterogeneity. Data Extraction and Synthesis: Random-effects meta-regression, with placebo and blinding as a fixed effect and intervention and end point grouping as random effects, was used to calculate the impact of placebo control for each end point. Data were analyzed from March 2019 to March 2020. Main Outcomes and Measures: End points were examined in prespecified subgroups: patient-reported or health care professional-assessed outcomes, quality of life, pain, blood pressure, exercise-related outcomes, recurrent bleeding, and all-cause mortality. Results: Ninety-seven end points were matched from 72 blinded, placebo-controlled trials (hereafter, blinded) and 55 unblinded trials without placebo control (hereafter, unblinded), including 111 500 individual patient end points. Unblinded trials had larger standardized effect sizes than blinded trials for exercise-related outcomes (standardized mean difference [SMD], 0.59; 95% CI, 0.29 to 0.89; P < .001) and quality-of-life (SMD, 0.32; 95% CI, 0.11 to 0.53; P = .003) and health care professional-assessed end points (SMD, 0.40; 95% CI, 0.18 to 0.61; P < .001). The placebo effect accounted for 88.1%, 55.2%, and 61.3% of the observed unblinded effect size for these end points, respectively. There was no significant difference between unblinded and blinded trials for patient-reported end points (SMD, 0.31; 95% CI, -0.02 to 0.64; P = .07), blood pressure (SMD, 0.26; 95% CI, -0.10 to 0.62; P = .15), all-cause mortality (odds ratio [OR], 0.23; 95% CI, -0.26 to 0.72; P = .36), pain (SMD, 0.03; 95% CI, -0.52 to 0.57; P = .91), or recurrent bleeding events (OR, -0.12; 95% CI, -1.11 to 0.88; P = .88). Conclusions and Relevance: The magnitude of the placebo effect found in this systematic review and meta-regression was dependent on the end point. Placebo control in trials of procedural interventions had the greatest impact on exercise-related, quality-of-life, and health care professional-assessed end points. Randomized clinical trials of procedural interventions may consider placebo control accordingly.

Therapeutic potential of conduction system pacing as a method for improving cardiac output during ventricular tachycardia.

BACKGROUND: Ventricular tachycardia (VT) reduces cardiac output through high heart rates, loss of atrioventricular synchrony, and loss of ventricular synchrony. We studied the contribution of each mechanism and explored the potential therapeutic utility of His bundle pacing to improve cardiac output during VT. METHODS: Study 1 aimed to improve the understanding of mechanisms of harm during VT (using pacing simulated VT). In 23 patients with left ventricular impairment, we recorded continuous ECG and beat-by-beat blood pressure measurements. We assessed the hemodynamic impact of heart rate and restoration of atrial and biventricular synchrony. Study 2 investigated novel pacing interventions during clinical VT by evaluating the hemodynamic effects of His bundle pacing at 5 bpm above the VT rate in 10 patients. RESULTS: In Study 1, at progressively higher rates of simulated VT, systolic blood pressure declined: at rates of 125, 160, and 190 bpm, -22.2%, -42.0%, and -58.7%, respectively (ANOVA p < 0.0001). Restoring atrial synchrony alone had only a modest beneficial effect on systolic blood pressure (+ 3.6% at 160 bpm, p = 0.2117), restoring biventricular synchrony alone had a greater effect (+ 9.1% at 160 bpm, p = 0.242), and simultaneously restoring both significantly increased systolic blood pressure (+ 31.6% at 160 bpm, p = 0.0003). In Study 2, the mean rate of clinical VT was 143 ± 21 bpm. His bundle pacing increased systolic blood pressure by + 14.2% (p = 0.0023). In 6 of 10 patients, VT terminated with His bundle pacing. CONCLUSIONS: Restoring atrial and biventricular synchrony improved hemodynamic function in simulated and clinical VT. Conduction system pacing could improve VT tolerability and treatment.

Active learning for left ventricle segmentation in echocardiography.

BACKGROUND AND OBJECTIVE: Training deep learning models for medical image segmentation require large annotated datasets, which can be expensive and time-consuming to create. Active learning is a promising approach to reduce this burden by strategically selecting the most informative samples for segmentation. This study investigates the use of active learning for efficient left ventricle segmentation in echocardiography with sparse expert annotations. METHODS: We adapt and evaluate various sampling techniques, demonstrating their effectiveness in judiciously selecting samples for segmentation. Additionally, we introduce a novel strategy, Optimised Representativeness Sampling, which combines feature-based outliers with the most representative samples to enhance annotation efficiency. RESULTS: Our findings demonstrate a substantial reduction in annotation costs, achieving a remarkable 99% upper bound performance while utilising only 20% of the labelled data. This equates to a reduction of 1680 images needing annotation within our dataset. When applied to a publicly available dataset, our approach yielded a remarkable 70% reduction in required annotation efforts, representing a significant advancement compared to baseline active learning strategies, which achieved only a 50% reduction. Our experiments highlight the nuanced performance of diverse sampling strategies across datasets within the same domain. CONCLUSIONS: The study provides a cost-effective approach to tackle the challenges of limited expert annotations in echocardiography. By introducing a distinct dataset, made publicly available for research purposes, our work contributes to the field's understanding of efficient annotation strategies in medical image segmentation.

Automated echocardiographic left ventricular dimension assessment in dogs using artificial intelligence: Development and validation.

BACKGROUND: Artificial intelligence (AI) could improve accuracy and reproducibility of echocardiographic measurements in dogs. HYPOTHESIS: A neural network can be trained to measure echocardiographic left ventricular (LV) linear dimensions in dogs. ANIMALS: Training dataset: 1398 frames from 461 canine echocardiograms from a single specialist center. VALIDATION: 50 additional echocardiograms from the same center. METHODS: Training dataset: a right parasternal 4-chamber long axis frame from each study, labeled by 1 of 18 echocardiographers, marking anterior and posterior points of the septum and free wall. VALIDATION DATASET: End-diastolic and end-systolic frames from 50 studies, annotated twice (blindly) by 13 experts, producing 26 measurements of each site from each frame. The neural network also made these measurements. We quantified its accuracy as the deviation from the expert consensus, using the individual-expert deviation from consensus as context for acceptable variation. The deviation of the AI measurement away from the expert consensus was assessed on each individual frame and compared with the root-mean-square-variation of the individual expert opinions away from that consensus. RESULTS: For the septum in end-diastole, individual expert opinions deviated by 0.12 cm from the consensus, while the AI deviated by 0.11 cm (P = .61). For LVD, the corresponding values were 0.20 cm for experts and 0.13 cm for AI (P = .65); for the free wall, experts 0.20 cm, AI 0.13 cm (P < .01). In end-systole, there were no differences between individual expert and AI performances. CONCLUSIONS AND CLINICAL IMPORTANCE: An artificial intelligence network can be trained to adequately measure linear LV dimensions, with performance indistinguishable from that of experts.

Automated mitral inflow Doppler peak velocity measurement using deep learning.

Doppler echocardiography is a widely utilised non-invasive imaging modality for assessing the functionality of heart valves, including the mitral valve. Manual assessments of Doppler traces by clinicians introduce variability, prompting the need for automated solutions. This study introduces an innovative deep learning model for automated detection of peak velocity measurements from mitral inflow Doppler images, independent from Electrocardiogram information. A dataset of Doppler images annotated by multiple expert cardiologists was established, serving as a robust benchmark. The model leverages heatmap regression networks, achieving 96% detection accuracy. The model discrepancy with the expert consensus falls comfortably within the range of inter- and intra-observer variability in measuring Doppler peak velocities. The dataset and models are open-source, fostering further research and clinical application.

A double-blind, randomised, placebo-controlled trial of the coronary sinus Reducer in refractory angina: design and rationale of the ORBITA-COSMIC trial.

The coronary sinus Reducer (CSR) is an hourglass-shaped device which creates an artificial stenosis in the coronary sinus. Whilst placebo-controlled data show an improvement in angina, these results are unreplicated and are the subject of further confirmatory research. The mechanism of action of this unintuitive therapy is unknown. The Coronary Sinus Reducer Objective Impact on Symptoms, MRI Ischaemia, and Microvascular Resistance (ORBITA-COSMIC) trial is a randomised, placebo-controlled, double-blind trial investigating the efficacy of the CSR. Patients with (i) established epicardial coronary artery disease, (ii) angina on maximally tolerated antianginal medication, (iii) evidence of myocardial ischaemia and (iv) no further options for percutaneous coronary intervention or coronary artery bypass grafting will be enrolled. Upon enrolment, angina and quality-of-life questionnaires, treadmill exercise testing and quantitative stress perfusion cardiac magnetic resonance (CMR) imaging will be performed. Participants will record their symptoms daily on a smartphone application throughout the trial. After a 2-week symptom assessment phase, participants will be randomised in the cardiac catheterisation laboratory to CSR or a placebo procedure. After 6 months of blinded follow-up, all prerandomisation tests will be repeated. A prespecified subgroup will undergo invasive coronary physiology assessment at prerandomisation and follow-up. The primary outcome is stress myocardial blood flow on CMR. Secondary outcomes include angina frequency, quality of life and treadmill exercise time. (ClinicalTrials.gov: NCT04892537).

The ability of contemporary cardiologists to judge the ischemic impact of a coronary lesion visually.

BACKGROUND: Landmark trials showed that invasive pressure measurement (Fractional Flow Reserve, FFR) was a better guide to coronary stenting than visual assessment. However, present-day interventionists have benefited from extensive research and personal experience of mapping anatomy to hemodynamics. AIMS: To determine if visual assessment of the angiogram performs as well as invasive measurement of coronary physiology. METHODS: 25 interventional cardiologists independently visually assessed the single vessel coronary disease of 200 randomized participants in The Objective Randomized Blinded Investigation with optimal medical Therapy of Angioplasty in stable angina trial (ORBITA). They gave a visual prediction of the FFR and Instantaneous Wave-free Ratio (iFR), denoted vFFR and viFR respectively. Each judged each lesion on 2 occasions, so that every lesion had 50 vFFR, and 50 viFR assessments. The group consensus visual estimates (vFFR-group and viFR-group) and individual cardiologists' visual estimates (vFFR-individual and viFR-individual) were tested alongside invasively measured FFR and iFR for their ability to predict the placebo-controlled reduction in stress echo ischemia with stenting. RESULTS: Placebo-controlled ischemia improvement with stenting was predicted by vFFR-group (p < 0.0001) and viFR-group (p < 0.0001), vFFR-individual (p < 0.0001) and viFR-individual (p < 0.0001). There were no significant differences between the predictive performance of the group visual estimates and their invasive counterparts: p = 0.53 for vFFR vs FFR and p = 0.56 for viFR vs iFR. CONCLUSION: Visual assessment of the angiogram by contemporary experts, provides significant additional information on the amount of ischaemia which can be relieved by placebo-controlled stenting in single vessel coronary artery disease.

Catheter Ablation for Ventricular Tachycardia After MI: A Reconstructed Individual Patient Data Meta-analysis of Randomised Controlled Trials.

Background: The prognostic impact of ventricular tachycardia (VT) catheter ablation is an important outstanding research question. We undertook a reconstructed individual patient data meta-analysis of randomised controlled trials comparing ablation to medical therapy in patients developing VT after MI. Methods: We systematically identified all trials comparing catheter ablation to medical therapy in patients with VT and prior MI. The prespecified primary endpoint was reconstructed individual patient assessment of all-cause mortality. Prespecified secondary endpoints included trial-level assessment of all-cause mortality, VT recurrence or defibrillator shocks and all-cause hospitalisations. Prespecified subgroup analysis was performed for ablation approaches involving only substrate modification without VT activation mapping. Sensitivity analyses were performed depending on the proportion of patients with prior MI included. Results: Eight trials, recruiting a total of 874 patients, were included. Of these 874 patients, 430 were randomised to catheter ablation and 444 were randomised to medical therapy. Catheter ablation reduced all-cause mortality compared with medical therapy when synthesising individual patient data (HR 0.63; 95% CI [0.41-0.96]; p=0.03), but not in trial-level analysis (RR 0.91; 95% CI [0.67-1.23]; p=0.53; I2=0%). Catheter ablation significantly reduced VT recurrence, defibrillator shocks and hospitalisations compared with medical therapy. Sensitivity analyses were consistent with the primary analyses. Conclusion: In patients with postinfarct VT, catheter ablation reduces mortality.

A Placebo-Controlled Trial of Percutaneous Coronary Intervention for Stable Angina.

BACKGROUND: Percutaneous coronary intervention (PCI) is frequently performed to reduce the symptoms of stable angina. Whether PCI relieves angina more than a placebo procedure in patients who are not receiving antianginal medication remains unknown. METHODS: We conducted a double-blind, randomized, placebo-controlled trial of PCI in patients with stable angina. Patients stopped all antianginal medications and underwent a 2-week symptom assessment phase before randomization. Patients were then randomly assigned in a 1:1 ratio to undergo PCI or a placebo procedure and were followed for 12 weeks. The primary end point was the angina symptom score, which was calculated daily on the basis of the number of angina episodes that occurred on a given day, the number of antianginal medications prescribed on that day, and clinical events, including the occurrence of unblinding owing to unacceptable angina or acute coronary syndrome or death. Scores range from 0 to 79, with higher scores indicating worse health status with respect to angina. RESULTS: A total of 301 patients underwent randomization: 151 to the PCI group and 150 to the placebo group. The mean (±SD) age was 64±9 years, and 79% were men. Ischemia was present in one cardiac territory in 242 patients (80%), in two territories in 52 patients (17%), and in three territories in 7 patients (2%). In the target vessels, the median fractional flow reserve was 0.63 (interquartile range, 0.49 to 0.75), and the median instantaneous wave-free ratio was 0.78 (interquartile range, 0.55 to 0.87). At the 12-week follow-up, the mean angina symptom score was 2.9 in the PCI group and 5.6 in the placebo group (odds ratio, 2.21; 95% confidence interval, 1.41 to 3.47; P<0.001). One patient in the placebo group had unacceptable angina leading to unblinding. Acute coronary syndromes occurred in 4 patients in the PCI group and in 6 patients in the placebo group. CONCLUSIONS: Among patients with stable angina who were receiving little or no antianginal medication and had objective evidence of ischemia, PCI resulted in a lower angina symptom score than a placebo procedure, indicating a better health status with respect to angina. (Funded by the National Institute for Health and Care Research Imperial Biomedical Research Centre and others; ORBITA-2 ClinicalTrials.gov number, NCT03742050.).