Publications by authors named "Matthew J Shun-Shin"

52 Publications

Multibeat echocardiographic phase detection using deep neural networks.

Comput Biol Med 2021 Apr 6;133:104373. Epub 2021 Apr 6.

School of Computing and Engineering, University of West London, London, United Kingdom; National Heart and Lung Institute, Imperial College, London, United Kingdom.

Background: Accurate identification of end-diastolic and end-systolic frames in echocardiographic cine loops is important, yet challenging, for human experts. Manual frame selection is subject to uncertainty, affecting crucial clinical measurements, such as myocardial strain. Therefore, the ability to automatically detect frames of interest is highly desirable.

Methods: We have developed deep neural networks, trained and tested on multi-centre patient data, for the accurate identification of end-diastolic and end-systolic frames in apical four-chamber 2D multibeat cine loop recordings of arbitrary length. Seven experienced cardiologist experts independently labelled the frames of interest, thereby providing infallible annotations, allowing for observer variability measurements.

Results: When compared with the ground-truth, our model shows an average frame difference of -0.09 ± 1.10 and 0.11 ± 1.29 frames for end-diastolic and end-systolic frames, respectively. When applied to patient datasets from a different clinical site, to which the model was blind during its development, average frame differences of -1.34 ± 3.27 and -0.31 ± 3.37 frames were obtained for both frames of interest. All detection errors fall within the range of inter-observer variability: [-0.87, -5.51]±[2.29, 4.26] and [-0.97, -3.46]±[3.67, 4.68] for ED and ES events, respectively.

Conclusions: The proposed automated model can identify multiple end-systolic and end-diastolic frames in echocardiographic videos of arbitrary length with performance indistinguishable from that of human experts, but with significantly shorter processing time.
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http://dx.doi.org/10.1016/j.compbiomed.2021.104373DOI Listing
April 2021

Reusable snorkel masks adapted as particulate respirators.

PLoS One 2021 5;16(4):e0249201. Epub 2021 Apr 5.

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Introduction: During viral pandemics, filtering facepiece (FFP) masks together with eye protection form the essential components of personal protective equipment (PPE) for healthcare workers. There remain concerns regarding insufficient global supply and imperfect protection offered by currently available PPE strategies. A range of full-face snorkel masks were adapted to accept high grade medical respiratory filters using bespoke-designed 3D-printed connectors. We compared the protection offered by the snorkel to that of standard PPE using a placebo-controlled respirator filtering test as well as a fluorescent droplet deposition experiment. Out of the 56 subjects tested, 42 (75%) passed filtering testing with the snorkel mask compared to 31 (55%) with a FFP3 respirator mask (p = 0.003). Amongst the 43 subjects who were not excluded following a placebo control, 85% passed filtering testing with the snorkel versus to 68% with a FFP3 mask (p = 0.008). Following front and lateral spray of fluorescence liquid particles, the snorkel mask also provided superior protection against droplet deposition within the subject's face, when compared to a standard PPE combination of FFP3 masks and eye protection (3.19x108 versus 6.81x108 fluorescence units, p<0.001). The 3D printable adaptors are available for free download online at https://www.ImperialHackspace.com/COVID-19-Snorkel-Respirator-Project/.

Conclusion: Full-face snorkel masks adapted as particulate respirators performed better than a standard PPE combination of FFP3 mask and eye protection against aerosol inhalation and droplet deposition. This adaptation is therefore a promising PPE solution for healthcare workers during highly contagious viral outbreaks.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0249201PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8021169PMC
April 2021

Electrocardiographic predictors of successful resynchronization of left bundle branch block by His bundle pacing.

J Cardiovasc Electrophysiol 2021 Feb 4;32(2):428-438. Epub 2021 Jan 4.

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

Background: His bundle pacing (HBP) is an alternative to biventricular pacing (BVP) for delivering cardiac resynchronization therapy (CRT) in patients with heart failure and left bundle branch block (LBBB). It is not known whether ventricular activation times and patterns achieved by HBP are equivalent to intact conduction systems and not all patients with LBBB are resynchronized by HBP.

Objective: To compare activation times and patterns of His-CRT with BVP-CRT, LBBB and intact conduction systems.

Methods: In patients with LBBB, noninvasive epicardial mapping (ECG imaging) was performed during BVP and temporary HBP. Intrinsic activation was mapped in all subjects. Left ventricular activation times (LVAT) were measured and epicardial propagation mapping (EPM) was performed, to visualize epicardial wavefronts. Normal activation pattern and a normal LVAT range were determined from normal subjects.

Results: Forty-five patients were included, 24 with LBBB and LV impairment, and 21 with normal 12-lead ECG and LV function. In 87.5% of patients with LBBB, His-CRT successfully shortened LVAT by ≥10 ms. In 33.3%, His-CRT resulted in complete ventricular resynchronization, with activation times and patterns indistinguishable from normal subjects. EPM identified propagation discontinuity artifacts in 83% of patients with LBBB. This was the best predictor of whether successful resynchronization was achieved by HBP (logarithmic odds ratio, 2.19; 95% confidence interval, 0.07-4.31; p = .04).

Conclusion: Noninvasive electrocardiographic mapping appears to identify patients whose LBBB can be resynchronized by HBP. In contrast to BVP, His-CRT may deliver the maximum potential ventricular resynchronization, returning activation times, and patterns to those seen in normal hearts.
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http://dx.doi.org/10.1111/jce.14845DOI Listing
February 2021

Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions.

Europace 2021 Feb;23(2):305-312

Institute of Cardiovascular Science, University College London & Bart's Heart Centre, Bart's Health NHS Trust, London, UK.

Aims : Rate adaptation of the action potential ensures spatial heterogeneities in conduction across the myocardium are minimized at different heart rates providing a protective mechanism against ventricular fibrillation (VF) and sudden cardiac death (SCD), which can be quantified by the ventricular conduction stability (V-CoS) test previously described. We tested the hypothesis that patients with a history of aborted SCD due to an underlying channelopathy or cardiomyopathy have a reduced capacity to maintain uniform activation following exercise.

Methods And Results : Sixty individuals, with (n = 28) and without (n = 32) previous aborted-SCD event underwent electro-cardiographic imaging recordings following exercise treadmill test. These included 25 Brugada syndrome, 13 hypertrophic cardiomyopathy, 12 idiopathic VF, and 10 healthy controls. Data were inputted into the V-CoS programme to calculate a V-CoS score that indicate the percentage of ventricle that showed no significant change in ventricular activation, with a lower score indicating the development of greater conduction heterogeneity. The SCD group, compared to those without, had a lower median (interquartile range) V-CoS score at peak exertion [92.8% (89.8-96.3%) vs. 97.3% (94.9-99.1%); P < 0.01] and 2 min into recovery [95.2% (91.1-97.2%) vs. 98.9% (96.9-99.5%); P < 0.01]. No significant difference was observable later into recovery at 5 or 10 min. Using the lowest median V-CoS scores obtained during the entire recovery period post-exertion, SCD survivors had a significantly lower score than those without for each of the different underlying aetiologies.

Conclusion : Data from this pilot study demonstrate the potential use of this technique in risk stratification for the inherited cardiac conditions.
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http://dx.doi.org/10.1093/europace/euaa248DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7868885PMC
February 2021

Within-patient comparison of His-bundle pacing, right ventricular pacing, and right ventricular pacing avoidance algorithms in patients with PR prolongation: Acute hemodynamic study.

J Cardiovasc Electrophysiol 2020 11 5;31(11):2964-2974. Epub 2020 Oct 5.

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

Aims: A prolonged PR interval may adversely affect ventricular filling and, therefore, cardiac function. AV delay can be corrected using right ventricular pacing (RVP), but this induces ventricular dyssynchrony, itself harmful. Therefore, in intermittent heart block, pacing avoidance algorithms are often implemented. We tested His-bundle pacing (HBP) as an alternative.

Methods: Outpatients with a long PR interval (>200 ms) and intermittent need for ventricular pacing were recruited. We measured within-patient differences in high-precision hemodynamics between AV-optimized RVP and HBP, as well as a pacing avoidance algorithm (Managed Ventricular Pacing [MVP]).

Results: We recruited 18 patients. Mean left ventricular ejection fraction was 44.3 ± 9%. Mean intrinsic PR interval was 266 ± 42 ms and QRS duration was 123 ± 29 ms. RVP lengthened QRS duration (+54 ms, 95% CI 42-67 ms, p < .0001) while HBP delivered a shorter QRS duration than RVP (-56 ms, 95% CI -67 to -46 ms, p < .0001). HBP did not increase QRS duration (-2 ms, 95% CI -8 to 13 ms, p = .6). HBP improved acute systolic blood pressure by mean of 5.0 mmHg (95% CI 2.8-7.1 mmHg, p < .0001) compared to RVP and by 3.5 mmHg (95% CI 1.9-5.0 mmHg, p = .0002) compared to the pacing avoidance algorithm. There was no significant difference in hemodynamics between RVP and ventricular pacing avoidance (p = .055).

Conclusions: HBP provides better acute cardiac function than pacing avoidance algorithms and RVP, in patients with prolonged PR intervals. HBP allows normalization of prolonged AV delays (unlike pacing avoidance) and does not cause ventricular dyssynchrony (unlike RVP). Clinical trials may be justified to assess whether these acute improvements translate into longer term clinical benefits in patients with bradycardia indications for pacing.
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http://dx.doi.org/10.1111/jce.14763DOI Listing
November 2020

Discriminating electrocardiographic responses to His-bundle pacing using machine learning.

Cardiovasc Digit Health J 2020 Jul-Aug;1(1):11-20

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Background: His-bundle pacing (HBP) has emerged as an alternative to conventional ventricular pacing because of its ability to deliver physiological ventricular activation. Pacing at the His bundle produces different electrocardiographic (ECG) responses: selective His-bundle pacing (S-HBP), non-selective His bundle pacing (NS-HBP), and myocardium-only capture (MOC). These 3 capture types must be distinguished from each other, which can be challenging and time-consuming even for experts.

Objective: The purpose of this study was to use artificial intelligence (AI) in the form of supervised machine learning using a convolutional neural network (CNN) to automate HBP ECG interpretation.

Methods: We identified patients who had undergone HBP and extracted raw 12-lead ECG data during S-HBP, NS-HBP, and MOC. A CNN was trained, using 3-fold cross-validation, on 75% of the segmented QRS complexes labeled with their capture type. The remaining 25% was kept aside as a testing dataset.

Results: The CNN was trained with 1297 QRS complexes from 59 patients. Cohen kappa for the neural network's performance on the 17-patient testing set was 0.59 (95% confidence interval 0.30 to 0.88; <.0001), with an overall accuracy of 75%. The CNN's accuracy in the 17-patient testing set was 67% for S-HBP, 71% for NS-HBP, and 84% for MOC.

Conclusion: We demonstrated proof of concept that a neural network can be trained to automate discrimination between HBP ECG responses. When a larger dataset is trained to higher accuracy, automated AI ECG analysis could facilitate HBP implantation and follow-up and prevent complications resulting from incorrect HBP ECG analysis.
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http://dx.doi.org/10.1016/j.cvdhj.2020.07.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7484933PMC
September 2020

Inter-observer differences in interpretation of coronary pressure-wire pullback data by non-expert interventional cardiologists.

Cardiovasc Interv Ther 2020 May 19. Epub 2020 May 19.

Hammersmith Hospital, Imperial College London, London, UK.

The physiological pattern of coronary artery disease as determined by pressure-wire (PW)-pullback is important for decision-making of revascularization and risk stratification of patients. However, it remains unclear whether inter-observer differences in interpreting PW-pullback data are subject to the expertise of physicians. This study sought to investigate the subjectivity of this assessment among non-experts. Expert interventional cardiologists classified 545 PW-pullback traces into physiologically focal or physiologically diffuse disease pattern. Defining expert-consensus as the reference standard, we evaluated ten non-expert doctors' classification performance. Observers were stratified equally by two ways: (i) years of experience as interventional cardiologists (middle-level vs. junior-level) and (ii) volume of institutions where they belonged to (high-volume center vs. low-volume center). When judged against the expert-consensus, the agreement of non-expert observers in assessing physiological pattern of disease (focal or diffuse) ranged from 69.1 to 85.0% (p for heterogeneity < 0.0001). There was no evidence for a moderating effect of years of experience; the pooled accuracy of middle-level doctors was 78.8% (95% confidential interval [CI] 72.8-84.7%) vs. 79.1% for junior-level doctors (95% CI 75.9-82.2%, p = 0.95 for difference). On the other hand, we observed a significant moderating effect of center volume. Accuracy across non-experts in high-volume centers was 82.7% (95% CI 80.3-85.1%) vs. 75.1% for low-volume centers (95% CI 71.9-78.3%, p = 0.0002 for difference). Interpretation of PW-pullback by non-expert interventional cardiologists was considerably subjective.
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http://dx.doi.org/10.1007/s12928-020-00673-3DOI Listing
May 2020

Improving ultrasound video classification: an evaluation of novel deep learning methods in echocardiography.

J Med Artif Intell 2020 Mar;3

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, London, UK.

Echocardiography is the commonest medical ultrasound examination, but automated interpretation is challenging and hinges on correct recognition of the 'view' (imaging plane and orientation). Current state-of-the-art methods for identifying the view computationally involve 2-dimensional convolutional neural networks (CNNs), but these merely classify individual frames of a video in isolation, and ignore information describing the movement of structures throughout the cardiac cycle. Here we explore the efficacy of novel CNN architectures, including time-distributed networks and two-stream networks, which are inspired by advances in human action recognition. We demonstrate that these new architectures more than halve the error rate of traditional CNNs from 8.1% to 3.9%. These advances in accuracy may be due to these networks' ability to track the movement of specific structures such as heart valves throughout the cardiac cycle. Finally, we show the accuracies of these new state-of-the-art networks are approaching expert agreement (3.6% discordance), with a similar pattern of discordance between views.
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http://dx.doi.org/10.21037/jmai.2019.10.03DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7100611PMC
March 2020

Dobutamine Stress Echocardiography Ischemia as a Predictor of the Placebo-Controlled Efficacy of Percutaneous Coronary Intervention in Stable Coronary Artery Disease: The Stress Echocardiography-Stratified Analysis of ORBITA.

Circulation 2019 12 11;140(24):1971-1980. Epub 2019 Nov 11.

Imperial College Healthcare NHS Trust, London, UK (R.K.A-L., M.J.S.-S., J.P.H., A.N.N., C.R., S.S., S.N., R.P., I.M., C.C., Y.A., H.S., R.A., G.C., G.K., J.M., J.E.D., D.P.F.).

Background: Dobutamine stress echocardiography is widely used to test for ischemia in patients with stable coronary artery disease. In this analysis, we studied the ability of the prerandomization stress echocardiography score to predict the placebo-controlled efficacy of percutaneous coronary intervention (PCI) within the ORBITA trial (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina).

Methods: One hundred eighty-three patients underwent dobutamine stress echocardiography before randomization. The stress echocardiography score is broadly the number of segments abnormal at peak stress, with akinetic segments counting double and dyskinetic segments counting triple. The ability of prerandomization stress echocardiography to predict the placebo-controlled effect of PCI on response variables was tested by using regression modeling.

Results: At prerandomization, the stress echocardiography score was 1.56±1.77 in the PCI arm (n=98) and 1.61±1.73 in the placebo arm (n=85). There was a detectable interaction between prerandomization stress echocardiography score and the effect of PCI on angina frequency score with a larger placebo-controlled effect in patients with the highest stress echocardiography score (=0.031). With our sample size, we were unable to detect an interaction between stress echocardiography score and any other patient-reported response variables: freedom from angina (=0.116), physical limitation (=0.461), quality of life (=0.689), EuroQOL 5 quality-of-life score (=0.789), or between stress echocardiography score and physician-assessed Canadian Cardiovascular Society angina class (=0.693), and treadmill exercise time (=0.426).

Conclusions: The degree of ischemia assessed by dobutamine stress echocardiography predicts the placebo-controlled efficacy of PCI on patient-reported angina frequency. The greater the downstream stress echocardiography abnormality caused by a stenosis, the greater the reduction in symptoms from PCI.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02062593.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.119.042918DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6903430PMC
December 2019

His bundle pacing, learning curve, procedure characteristics, safety, and feasibility: Insights from a large international observational study.

J Cardiovasc Electrophysiol 2019 10 2;30(10):1984-1993. Epub 2019 Aug 2.

National Heart and Lung Institute, Imperial College London, London.

Background: His-bundle pacing (HBP) provides physiological ventricular activation. Observational studies have demonstrated the techniques' feasibility; however, data have come from a limited number of centers.

Objectives: We set out to explore the contemporary global practice in HBP focusing on the learning curve, procedural characteristics, and outcomes.

Methods: This is a retrospective, multicenter observational study of patients undergoing attempted HBP at seven centers. Pacing indication, fluoroscopy time, HBP thresholds, and lead reintervention and deactivation rates were recorded. Where centers had systematically recorded implant success rates from the outset, these were collated.

Results: A total of 529 patients underwent attempted HBP during the study period (2014-19) with a mean follow-up of 217 ± 303 days. Most implants were for bradycardia indications. In the three centers with the systematic collation of all attempts, the overall implant success rate was 81%, which improved to 87% after completion of 40 cases. All seven centers reported data on successful implants. The mean fluoroscopy time was 11.7 ± 12.0 minutes, the His-bundle capture threshold at implant was 1.4 ± 0.9 V at 0.8 ± 0.3 ms, and it was 1.3 ± 1.2 V at 0.9 ± 0.2 ms at last device check. HBP lead reintervention or deactivation (for lead displacement or rise in threshold) occurred in 7.5% of successful implants. There was evidence of a learning curve: fluoroscopy time and HBP capture threshold reduced with greater experience, plateauing after approximately 30-50 cases.

Conclusion: We found that it is feasible to establish a successful HBP program, using the currently available implantation tools. For physicians who are experienced at pacemaker implantation, the steepest part of the learning curve appears to be over the first 30-50 cases.
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http://dx.doi.org/10.1111/jce.14064DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7038224PMC
October 2019

Quantification of Electromechanical Coupling to Prevent Inappropriate Implantable Cardioverter-Defibrillator Shocks.

JACC Clin Electrophysiol 2019 06 27;5(6):705-715. Epub 2019 Mar 27.

Department of Cardiology, Imperial College Hospitals National Health Service Trust, London, United Kingdom; National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Objectives: This study sought to test specialized processing of laser Doppler signals for discriminating ventricular fibrillation (VF) from common causes of inappropriate therapies.

Background: Inappropriate implantable cardioverter-defibrillator (ICD) therapies remain a clinically important problem associated with morbidity and mortality. Tissue perfusion biomarkers, implemented to assist automated diagnosis of VF, sometimes mistake artifacts and random noise for perfusion, which could lead to shocks being inappropriately withheld.

Methods: The study tested a novel processing algorithm that combines electrogram data and laser Doppler perfusion monitoring as a method for assessing circulatory status. Fifty patients undergoing VF induction during ICD implantation were recruited. Noninvasive laser Doppler and continuous electrograms were recorded during both sinus rhythm and VF. Two additional scenarios that might have led to inappropriate shocks were simulated for each patient: ventricular lead fracture and T-wave oversensing. The laser Doppler was analyzed using 3 methods for reducing noise: 1) running mean; 2) oscillatory height; and 3) a novel quantification of electromechanical coupling which gates laser Doppler relative to electrograms. In addition, the algorithm was tested during exercise-induced sinus tachycardia.

Results: Only the electromechanical coupling algorithm found a clear perfusion cut off between sinus rhythm and VF (sensitivity and specificity of 100%). Sensitivity and specificity remained at 100% during simulated lead fracture and electrogram oversensing. (Area under the curve running mean: 0.91; oscillatory height: 0.86; electromechanical coupling: 1.00). Sinus tachycardia did not cause false positive results.

Conclusions: Quantifying the coupling between electrical and perfusion signals increases reliability of discrimination between VF and artifacts that ICDs may interpret as VF. Incorporating such methods into future ICDs may safely permit reductions of inappropriate shocks.
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http://dx.doi.org/10.1016/j.jacep.2019.01.025DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6597902PMC
June 2019

Cardiac Rhythm Device Identification Using Neural Networks.

JACC Clin Electrophysiol 2019 05 27;5(5):576-586. Epub 2019 Mar 27.

Department of Cardiology, National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Objectives: This paper reports the development, validation, and public availability of a new neural network-based system which attempts to identify the manufacturer and even the model group of a pacemaker or defibrillator from a chest radiograph.

Background: Medical staff often need to determine the model of a pacemaker or defibrillator (cardiac rhythm device) quickly and accurately. Current approaches involve comparing a device's radiographic appearance with a manual flow chart.

Methods: In this study, radiographic images of 1,676 devices, comprising 45 models from 5 manufacturers were extracted. A convolutional neural network was developed to classify the images, using a training set of 1,451 images. The testing set contained an additional 225 images consisting of 5 examples of each model. The network's ability to identify the manufacturer of a device was compared with that of cardiologists, using a published flowchart.

Results: The neural network was 99.6% (95% confidence interval [CI]: 97.5% to 100.0%) accurate in identifying the manufacturer of a device from a radiograph and 96.4% (95% CI: 93.1% to 98.5%) accurate in identifying the model group. Among 5 cardiologists who used the flowchart, median identification of manufacturer accuracy was 72.0% (range 62.2% to 88.9%), and model group identification was not possible. The network's ability to identify the manufacturer of the devices was significantly superior to that of all the cardiologists (p < 0.0001 compared with the median human identification; p < 0.0001 compared with the best human identification).

Conclusions: A neural network can accurately identify the manufacturer and even model group of a cardiac rhythm device from a radiograph and exceeds human performance. This system may speed up the diagnosis and treatment of patients with cardiac rhythm devices, and it is publicly accessible online.
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http://dx.doi.org/10.1016/j.jacep.2019.02.003DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6537849PMC
May 2019

How to deliver personalized cardiac resynchronization therapy through the precise measurement of the acute hemodynamic response: Insights from the iSpot trial.

J Cardiovasc Electrophysiol 2019 09 25;30(9):1610-1619. Epub 2019 Jun 25.

International Centre for Circulatory Health, Imperial College London, Hammersmith Hospital, London, United Kingdom.

Introduction: New pacing technologies offer a greater choice of left ventricular pacing sites and greater personalization of cardiac resynchronization therapy (CRT). The effects on cardiac function of novel pacing configurations are often compared using multi-beat averages of acute hemodynamic measurements. In this analysis of the iSpot trial, we explore whether this is sufficient.

Materials And Methods: The iSpot trial was an international, prospective, acute hemodynamic trial that assessed seven CRT configurations: standard CRT, MultiSpot (posterolateral vein), and MultiVein (anterior and posterior vein) pacing. Invasive and noninvasive blood pressure, and left ventricular (LV) dP/dt were recorded. Eight beats were recorded before and after an alternation from AAI to the tested pacing configuration and vice-versa. Eight alternations were performed for each configuration at each of the five atrioventricular delays.

Results: Twenty-five patients underwent the full protocol of eight alternations. Only four (16%) patients had a statistically significant >3 mm Hg improvement over conventional CRT configuration (posterolateral vein, distal electrode). However, if only one alternation was analyzed (standard multi-beat averaging protocol), 15 (60%) patients falsely appeared to have a superior nonconventional configuration. Responses to pacing were significantly correlated between the different hemodynamic measures: invasive systolic blood pressure (SBP) vs noninvasive SBP r = 0.82 (P < .001); invasive SBP vs LV dP/dt r = 0.57, r  = 0.32 (P < .001).

Conclusions: Current standard multibeat acquisition protocols are unfortunately unable to prevent false impressions of optimality arising in individual patients. Personalization processes need to include distinct repeated transitions to the tested pacing configuration in addition to averaging multiple beats. The need is not only during research stages but also during clinical implementation.
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http://dx.doi.org/10.1111/jce.14001DOI Listing
September 2019

Physiological Pattern of Disease Assessed by Pressure-Wire Pullback Has an Influence on Fractional Flow Reserve/Instantaneous Wave-Free Ratio Discordance.

Circ Cardiovasc Interv 2019 05;12(5):e007494

International Center for Circulatory Health, National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, United Kingdom (T.W., C.M.C., J.P.H., Y.A., M.J.S.-S., R.P., S.S., S.N., R.A.L., D.P.F., J.E.D.).

Background: Fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) disagree on the hemodynamic significance of a coronary lesion in ≈20% of cases. It is unknown whether the physiological pattern of disease is an influencing factor for this. This study assessed whether the physiological pattern of coronary artery disease influences discordance between FFR and iFR measurement.

Methods And Results: Three-hundred and sixty intermediate coronary lesions (345 patients; mean age, 64.4±10.3 years; 76% men) with combined FFR, iFR, and iFR pressure-wire pullback were included for analysis from an international multicenter registry. Cut points for hemodynamic significance were FFR ≤0.80 and iFR ≤0.89, respectively. Lesions were classified into FFR+/iFR+ (n=154; 42.7%), FFR-/iFR+ (n=38; 10.6%), FFR+/iFR- (n=41; 11.4%), and FFR-/iFR- (n=127; 35.3%) groups. The physiological pattern of disease was classified according to the iFR pullback recordings as predominantly physiologically focal (n=171; 47.5%) or predominantly physiologically diffuse (n=189; 52.5%). Median FFR and iFR were 0.80 (interquartile range, 0.75-0.85) and 0.89 (interquartile range, 0.86-0.92), respectively. FFR disagreed with iFR in 22% (79 of 360). The physiological pattern of disease was the only influencing factor relating to FFR/iFR discordance: predominantly physiologically focal was significantly associated with FFR+/iFR- (58.5% [24 of 41]), and predominantly physiologically diffuse was significantly associated with FFR-/iFR+ (81.6% [31 of 38]; P<0.001 for pattern of disease between FFR+/iFR- and FFR-/iFR+ groups).

Conclusions: The physiological pattern of coronary artery disease was an important influencing factor for FFR/iFR discordance.
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http://dx.doi.org/10.1161/CIRCINTERVENTIONS.118.007494DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6553990PMC
May 2019

Association Between Physiological Stenosis Severity and Angina-Limited Exercise Time in Patients With Stable Coronary Artery Disease.

JAMA Cardiol 2019 06;4(6):569-574

Imperial College London, London, United Kingdom.

Importance: Physiological stenosis assessment is recommended to guide percutaneous coronary intervention (PCI) in patients with stable angina.

Objective: To determine the association between all commonly used indices of physiological stenosis severity and angina-limited exercise time in patients with stable angina.

Design, Setting, And Participants: This cohort study included data (without follow-up) collected over 1 year from 2 cardiac hospitals. Selected patients with stable angina and physiologically severe single-vessel coronary artery disease presenting for clinically driven elective PCI were included.

Exposures: Fractional flow reserve (FFR), instantaneous wave-free ratio (iFR), hyperemic stenosis resistance (HSR), and coronary flow reserve (CFR) were measured invasively. Immediately after this, patients maximally exercised on a catheter-table-mounted supine ergometer until they developed rate-limiting angina. Subsequent PCI was performed in most patients, followed by repeat maximal supine exercise testing.

Main Outcomes And Measures: Associations between FFR, iFR, HSR, CFR, and angina-limited exercise time were assessed using linear regression and Pearson correlation coefficients. Additionally, the associations between the post-PCI increment in exercise time and baseline FFR, iFR, HSR, and CFR were assessed.

Results: Twenty-three patients (21 [91.3%] of whom were male; mean [SD] age, 60.6 [8.1] years) completed the pre-PCI component of the study protocol. Mean (SD) stenosis diameter was 74.6% (10.4%). Median (interquartile range [IQR]) values were 0.54 (0.44-0.72) for FFR, 0.53 (0.38-0.83) for iFR, 1.67 (0.84-3.16) for HSR, and 1.35 (1.11-1.63) for CFR. Mean (SD) angina-limited exercise time was 144 (77) seconds. Anatomical stenosis characteristics were not significantly associated with angina-limited exercise time. Conversely, FFR (R2 = 0.27; P = .01), iFR (R2 = 0.46; P < .001), HSR (R2 = 0.39; P < .01), and CFR (R2 = 0.16; P < .05) were all associated with angina-limited exercise time. Twenty-one patients (19 [90.5%] of whom were male; mean [SD] age, 60.1 [8.2] years) competed the full protocol of PCI, post-PCI physiological assessment, and post-PCI maximal exercise. After PCI, the median (IQR) FFR rose to 0.91 (0.85-0.96), median (IQR) iFR to 0.98 (0.94-0.99), and median (IQR) CFR to 2.73 (2.50-3.12), while the median (IQR) HSR fell to 0.16 (0.06-0.37) (P < .001 for all). The post-PCI increment in exercise time was most significantly associated with baseline iFR (R2 = 0.26; P = .02).

Conclusions And Relevance: In a selected group of patients with severe, single-vessel stable angina, FFR, iFR, HSR, and CFR were all modestly correlated with angina-limited exercise time to varying degrees. Notwithstanding the limited sample size, no clear association was demonstrated between anatomical stenosis severity and angina-limited exercise time.
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http://dx.doi.org/10.1001/jamacardio.2019.1139DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6495364PMC
June 2019

Fractional flow reserve derived from microcatheters versus standard pressure wires: a stenosis-level meta-analysis.

Open Heart 2019;6(1):e000971. Epub 2019 Mar 25.

International Centre for Circulatory Health, Imperial College London, London, UK.

Aims: To determine the agreement between sensor-tipped microcatheter (MC) and pressure wire (PW)-derived fractional flow reserve (FFR).

Methods And Results: Studies comparing FFR obtained from MC (FFR, Navvus Microcatheter System, ACIST Medical Systems, Eden Prairie, Minnesota, USA) versus standard PW (FFR) were identified, and a meta-analysis of numerical and categorical agreement was performed. The relative levels of drift and device failure of MC and PW systems from each study were assessed. Six studies with 440 lesions (413 patients) were included. The mean overall bias between FFR and FFR was -0.029 (FFR lower). Bias and variance were greater for lesions with lower FFR (p<0.001). Using a cut-off of 0.80, 18 % of lesions were reclassified by FFR versus FFR (with 15 % being false positives). The difference in reported drift between FFR and FFR was small. Device failure was more common with MC than PW (7.1% vs 2%).

Conclusion: FFR systematically overestimates lesion severity, with increased bias in more severe lesions. Using FFR changes revascularisation guidance in approximately one out of every five cases. PW drift was similar between systems. Device failure was higher with MC.
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http://dx.doi.org/10.1136/openhrt-2018-000971DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6443142PMC
February 2021

Improving haemodynamic optimization of cardiac resynchronization therapy for heart failure.

Physiol Meas 2019 05 1;40(4):04NT01. Epub 2019 May 1.

Addenbrooke's Hospital, Cambridge University Hospitals NHS Trust, Hills Rd, Cambridge CB2 0QQ, United Kingdom.

Objective: Optimization of cardiac resynchronization therapy using non-invasive haemodynamic parameters produces reliable optima when performed at high atrial paced heart rates. Here we investigate whether this is a result of increased heart rate or atrial pacing itself.

Approach: Forty-three patients with cardiac resynchronization therapy underwent haemodynamic optimization of atrioventricular (AV) delay using non-invasive beat-to-beat systolic blood pressure in three states: rest (atrial-sensing, 66  ±  11 bpm), slow atrial pacing (73  ±  12 bpm), and fast atrial pacing (94  ±  10 bpm). A 20-patient subset underwent a fourth optimization, during exercise (80  ±  11 bpm).

Main Results: Intraclass correlation coefficient (ICC, quantifying information content mean  ±SE) was 0.20  ±  0.02 for resting sensed optimization, 0.45  ±  0.03 for slow atrial pacing (p   <  0.0001 versus rest-sensed), and 0.52  ±  0.03 for fast atrial pacing (p   =  0.12 versus slow-paced). 78% of the increase in ICC, from sinus rhythm to fast atrial pacing, is achieved by simply atrially pacing just above sinus rate. Atrial pacing increased signal (blood pressure difference between best and worst AV delay) from 6.5  ±  0.6 mmHg at rest to 13.3  ±  1.1 mmHg during slow atrial pacing (p   <  0.0001) and 17.2  ±  1.3 mmHg during fast atrial pacing (p   =  0.003 versus slow atrial pacing). Atrial pacing reduced noise (average SD of systolic blood pressure measurements) from 4.9  ±  0.4 mmHg at rest to 4.1  ±  0.3 mmHg during slow atrial pacing (p   =  0.28). At faster atrial pacing the noise was 4.6  ±  0.3 mmHg (p   =  0.69 versus slow-paced, p   =  0.90 versus rest-sensed). In the exercise subgroup ICC was 0.14  ±  0.02 (p   =  0.97 versus rest-sensed).

Significance: Atrial pacing, rather than the increase in heart rate, contributes to ~80% of the observed information content improvement from sinus rhythm to fast atrial pacing. This is predominantly through increase in measured signal.
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http://dx.doi.org/10.1088/1361-6579/ab152cDOI Listing
May 2019

Ventricular conduction stability test: a method to identify and quantify changes in whole heart activation patterns during physiological stress.

Europace 2019 Sep;21(9):1422-1431

National Heart & Lung Institute, Imperial College London, London, UK.

Aims: Abnormal rate adaptation of the action potential is proarrhythmic but is difficult to measure with current electro-anatomical mapping techniques. We developed a method to rapidly quantify spatial discordance in whole heart activation in response to rate cycle length changes. We test the hypothesis that patients with underlying channelopathies or history of aborted sudden cardiac death (SCD) have a reduced capacity to maintain uniform activation following exercise.

Methods And Results: Electrocardiographical imaging (ECGI) reconstructs >1200 electrograms (EGMs) over the ventricles from a single beat, providing epicardial whole heart activation maps. Thirty-one individuals [11 SCD survivors; 10 Brugada syndrome (BrS) without SCD; and 10 controls] with structurally normal hearts underwent ECGI vest recordings following exercise treadmill. For each patient, we calculated the relative change in EGM local activation times (LATs) between a baseline and post-exertion phase using custom written software. A ventricular conduction stability (V-CoS) score calculated to indicate the percentage of ventricle that showed no significant change in relative LAT (<10 ms). A lower score reflected greater conduction heterogeneity. Mean variability (standard deviation) of V-CoS score over 10 consecutive beats was small (0.9 ± 0.5%), with good inter-operator reproducibility of V-CoS scores. Sudden cardiac death survivors, compared to BrS and controls, had the lowest V-CoS scores post-exertion (P = 0.011) but were no different at baseline (P = 0.50).

Conclusion: We present a method to rapidly quantify changes in global activation which provides a measure of conduction heterogeneity and proof of concept by demonstrating SCD survivors have a reduced capacity to maintain uniform activation following exercise.
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http://dx.doi.org/10.1093/europace/euz015DOI Listing
September 2019

Right ventricular pacing for hypertrophic obstructive cardiomyopathy: meta-analysis and meta-regression of clinical trials.

Eur Heart J Qual Care Clin Outcomes 2019 10;5(4):321-333

National Heart and Lung Institute, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK.

Aims: Right ventricular pacing for left ventricular outflow tract gradient reduction in hypertrophic obstructive cardiomyopathy remains controversial. We undertook a meta-analysis for echocardiographic and functional outcomes.

Methods And Results: Thirty-four studies comprising 1135 patients met eligibility criteria. In the four blinded randomized controlled trials (RCTs), pacing reduced gradient by 35% [95% confidence interval (CI) 23.2-46.9, P < 0.0001], but there was only a trend towards improved New York Heart Association (NYHA) class [odds ratio (OR) 1.82, CI 0.96-3.44; P = 0.066]. The unblinded observational studies reported a 54.3% (CI 44.1-64.6, P < 0.0001) reduction in gradient, which was a 18.6% greater reduction than the RCTs (P = 0.0351 for difference between study designs). Observational studies reported an effect on unblinded NYHA class at an OR of 8.39 (CI 4.39-16.04, P < 0.0001), 450% larger than the OR in RCTs (P = 0.0042 for difference between study designs). Across all studies, the gradient progressively decreased at longer follow durations, by 5.2% per month (CI 2.5-7.9, P = 0.0001).

Conclusion: Right ventricular pacing reduces gradient in blinded RCTs. There is a non-significant trend to reduction in NYHA class. The bias in assessment of NYHA class in observational studies appears to be more than twice as large as any genuine treatment effect.
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http://dx.doi.org/10.1093/ehjqcco/qcz006DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6775860PMC
October 2019

His Resynchronization Versus Biventricular Pacing in Patients With Heart Failure and Left Bundle Branch Block.

J Am Coll Cardiol 2018 12;72(24):3112-3122

National Heart and Lung Institute, Imperial College London, London, United Kingdom.

Background: His bundle pacing is a new method for delivering cardiac resynchronization therapy (CRT).

Objectives: The authors performed a head-to-head, high-precision, acute crossover comparison between His bundle pacing and conventional biventricular CRT, measuring effects on ventricular activation and acute hemodynamic function.

Methods: Patients with heart failure and left bundle branch block referred for conventional biventricular CRT were recruited. Using noninvasive epicardial electrocardiographic imaging, the authors identified patients in whom His bundle pacing shortened left ventricular activation time. In these patients, the authors compared the hemodynamic effects of His bundle pacing against biventricular pacing using a high-multiple repeated alternation protocol to minimize the effect of noise, as well as comparing effects on ventricular activation.

Results: In 18 of 23 patients, left ventricular activation time was significantly shortened by His bundle pacing. Seventeen patients had a complete electromechanical dataset. In them, His bundle pacing was more effective at delivering ventricular resynchronization than biventricular pacing: greater reduction in QRS duration (-18.6 ms; 95% confidence interval [CI]: -31.6 to -5.7 ms; p = 0.007), left ventricular activation time (-26 ms; 95% CI: -41 to -21 ms; p = 0.002), and left ventricular dyssynchrony index (-11.2 ms; 95% CI: -16.8 to -5.6 ms; p < 0.001). His bundle pacing also produced a greater acute hemodynamic response (4.6 mm Hg; 95% CI: 0.2 to 9.1 mm Hg; p = 0.04). The incremental activation time reduction with His bundle pacing over biventricular pacing correlated with the incremental hemodynamic improvement with His bundle pacing over biventricular pacing (R = 0.70; p = 0.04).

Conclusions: His resynchronization delivers better ventricular resynchronization, and greater improvement in hemodynamic parameters, than biventricular pacing.
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http://dx.doi.org/10.1016/j.jacc.2018.09.073DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6290113PMC
December 2018

Outcomes of paroxysmal atrial fibrillation ablation studies are affected more by study design and patient mix than ablation technique.

J Cardiovasc Electrophysiol 2018 11 30;29(11):1471-1479. Epub 2018 Oct 30.

Department of Medicine, Royal Jubilee Hospital, Victoria, Canada.

Objective: We tested whether ablation methodology and study design can explain the varying outcomes in terms of atrial fibrillation (AF)-free survival at 1 year.

Background: There have been numerous paroxysmal AF ablation trials, which are heterogeneous in their use of different ablation techniques and study design. A useful approach to understanding how these factors influence outcome is to dismantle the trials into individual arms and reconstitute them as a large meta-regression.

Methods: Data were collected from 66 studies (6941 patients). With freedom from AF as the dependent variable, we performed meta-regression using the individual study arm as the unit.

Results: Success rates did not change regardless of the technique used to produce pulmonary vein isolation (PVI). Neither was adjunctive lesion sets associated with any improvement in outcome. Studies that included more males and fewer hypertensive patients were found more likely to report better outcomes. The electrocardiography method selected to assess outcome also plays an important role. Outcomes were worse in studies that used regular telemonitoring (by 23%; P < 0.001) or in patients who had implantable loop recorders (by 21%; P = 0.006), rather than those with the less thorough periodic Holter monitoring.

Conclusions: Outcomes of AF ablation studies involving PVI are not affected by the technologies used to produce PVI. Neither do adjunctive lesion sets change the outcome. Achieving high success rates in these studies appears to be dependent more on patient mix and on the thoroughness of AF detection protocols. These should be carefully considered when quoting the success rates of AF ablation procedures that are derived from such studies.
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http://dx.doi.org/10.1111/jce.13745DOI Listing
November 2018

Impact of Percutaneous Revascularization on Exercise Hemodynamics in Patients With Stable Coronary Disease.

J Am Coll Cardiol 2018 08;72(9):970-983

Imperial College London, London, United Kingdom. Electronic address:

Background: Recently, the therapeutic benefits of percutaneous coronary intervention (PCI) have been challenged in patients with stable coronary artery disease (SCD).

Objectives: The authors examined the impact of PCI on exercise responses in the coronary circulation, the microcirculation, and systemic hemodynamics in patients with SCD.

Methods: A total of 21 patients (mean age 60.3 ± 8.4 years) with SCD and single-vessel coronary stenosis underwent cardiac catheterization. Pre-PCI, patients exercised on a supine ergometer until rate-limiting angina or exhaustion. Simultaneous trans-stenotic coronary pressure-flow measurements were made throughout exercise. Post-PCI, this process was repeated. Physiological parameters, rate-limiting symptoms, and exercise performance were compared between pre-PCI and post-PCI exercise cycles.

Results: PCI reduced ischemia as documented by fractional flow reserve value (pre-PCI 0.59 ± 0.18 to post-PCI 0.91 ± 0.07), instantaneous wave-free ratio value (pre-PCI 0.61 ± 0.27 to post-PCI 0.96 ± 0.05) and coronary flow reserve value (pre-PCI 1.7 ± 0.7 to post-PCI 3.1 ± 1.0; p < 0.001 for all). PCI increased peak-exercise average peak coronary flow velocity (p < 0.0001), coronary perfusion pressure (distal coronary pressure; p < 0.0001), systolic blood pressure (p = 0.01), accelerating wave energy (p < 0.001), and myocardial workload (rate-pressure product; p < 0.01). These changes observed immediately following PCI resulted from the abolition of stenosis resistance (p < 0.0001). PCI was also associated with an immediate improvement in exercise time (+67 s; 95% confidence interval: 31 to 102 s; p < 0.0001) and a reduction in rate-limiting angina symptoms (81% reduction in rate-limiting angina symptoms post-PCI; p < 0.001).

Conclusions: In patients with SCD and severe single-vessel stenosis, objective physiological responses to exercise immediately normalize following PCI. This is seen in the coronary circulation, the microcirculation, and systemic hemodynamics.
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http://dx.doi.org/10.1016/j.jacc.2018.06.033DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6580361PMC
August 2018

Rationale and design of the randomized multicentre His Optimized Pacing Evaluated for Heart Failure (HOPE-HF) trial.

ESC Heart Fail 2018 10 9;5(5):965-976. Epub 2018 Jul 9.

Imperial College London, London, UK.

Aims: In patients with heart failure and a pathologically prolonged PR interval, left ventricular (LV) filling can be improved by shortening atrioventricular delay using His-bundle pacing. His-bundle pacing delivers physiological ventricular activation and has been shown to improve acute haemodynamic function in this group of patients. In the HOPE-HF (His Optimized Pacing Evaluated for Heart Failure) trial, we are investigating whether these acute haemodynamic improvements translate into improvements in exercise capacity and heart failure symptoms.

Methods And Results: This multicentre, double-blind, randomized, crossover study aims to randomize 160 patients with PR prolongation (≥200 ms), LV impairment (EF ≤ 40%), and either narrow QRS (≤140 ms) or right bundle branch block. All patients receive a cardiac device with leads positioned in the right atrium and the His bundle. Eligible patients also receive a defibrillator lead. Those not eligible for implantable cardioverter defibrillator have a backup pacing lead positioned in an LV branch of the coronary sinus. Patients are allocated in random order to 6 months of (i) haemodynamically optimized dual chamber His-bundle pacing and (ii) backup pacing only, using the non-His ventricular lead. The primary endpoint is change in exercise capacity assessed by peak oxygen uptake. Secondary endpoints include change in ejection fraction, quality of life scores, B-type natriuretic peptide, daily patient activity levels, and safety and feasibility assessments of His-bundle pacing.

Conclusions: Hope-HF aims to determine whether correcting PR prolongation in patients with heart failure and narrow QRS or right bundle branch block using haemodynamically optimized dual chamber His-bundle pacing improves exercise capacity and symptoms. We aim to complete recruitment by the end of 2018 and report in 2020.
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http://dx.doi.org/10.1002/ehf2.12315DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6165934PMC
October 2018

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

Circulation 2018 10;138(17):1780-1792

National Heart and Lung Institute, Imperial College London, United Kingdom (R.A-L., J.H., M.S.-S., D.T., S.S., S.N., R.P., I.M., C.C., Y.A., G.C., R.W., J.M., S.A.T., D.P.F.).

Background: There are no data on how fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR) are associated with the placebo-controlled efficacy of percutaneous coronary intervention (PCI) in stable single-vessel coronary artery disease.

Methods: We report the association between prerandomization invasive physiology within ORBITA (Objective Randomised Blinded Investigation With Optimal Medical Therapy of Angioplasty in Stable Angina), a placebo-controlled trial of patients who have stable angina with angiographically severe single-vessel coronary disease clinically eligible for PCI. Patients underwent prerandomization research FFR and iFR assessment. The operator was blinded to these values. Assessment of response variables, treadmill exercise time, stress echocardiography score, symptom frequency, and angina severity were performed at prerandomization and blinded follow-up. Effects were calculated by analysis of covariance. The ability of FFR and iFR to predict placebo-controlled changes in response variables was tested by using regression modeling.

Results: Invasive physiology data were available in 196 patients (103 PCI and 93 placebo). At prerandomization, the majority had Canadian Cardiovascular Society class II or III symptoms (150/196, 76.5%). Mean FFR and iFR were 0.69±0.16 and 0.76±0.22, respectively; 97% had ≥1 positive ischemia tests. The estimated effect of PCI on between-arm prerandomization-adjusted total exercise time was 20.7 s (95% confidence interval [CI], -4.0 to 45.5; P=0.100) with no interaction of FFR ( P=0.318) or iFR ( P=0.523). PCI improved stress echocardiography score more than placebo (1.07 segment units; 95% CI, 0.70-1.44; P<0.00001). The placebo-controlled effect of PCI on stress echocardiography score increased progressively with decreasing FFR ( P<0.00001) and decreasing iFR ( P<0.00001). PCI did not improve angina frequency score significantly more than placebo (odds ratio, 1.64; 95% CI, 0.96-2.80; P=0.072) with no detectable evidence of interaction with FFR ( P=0.849) or iFR ( P=0.783). However, PCI resulted in more patient-reported freedom from angina than placebo (49.5% versus 31.5%; odds ratio, 2.47; 95% CI, 1.30-4.72; P=0.006) but neither FFR ( P=0.693) nor iFR ( P=0.761) modified this effect.

Conclusions: In patients with stable angina and severe single-vessel disease, the blinded effect of PCI was more clearly seen by stress echocardiography score and freedom from angina than change in treadmill exercise time. Moreover, the lower the FFR or iFR, the greater the magnitude of stress echocardiographic improvement caused by PCI.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT02062593.
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http://dx.doi.org/10.1161/CIRCULATIONAHA.118.033801DOI Listing
October 2018

Association Between Use of Sodium-Glucose Cotransporter 2 Inhibitors, Glucagon-like Peptide 1 Agonists, and Dipeptidyl Peptidase 4 Inhibitors With All-Cause Mortality in Patients With Type 2 Diabetes: A Systematic Review and Meta-analysis.

JAMA 2018 04;319(15):1580-1591

Department of Endocrinology, Imperial College Healthcare NHS Foundation Trust, London, United Kingdom.

Importance: The comparative clinical efficacy of sodium-glucose cotransporter 2 (SGLT-2) inhibitors, glucagon-like peptide 1 (GLP-1) agonists, and dipeptidyl peptidase 4 (DPP-4) inhibitors for treatment of type 2 diabetes is unknown.

Objective: To compare the efficacies of SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors on mortality and cardiovascular end points using network meta-analysis.

Data Sources: MEDLINE, Embase, Cochrane Library Central Register of Controlled Trials, and published meta-analyses from inception through October 11, 2017.

Study Selection: Randomized clinical trials enrolling participants with type 2 diabetes and a follow-up of at least 12 weeks were included, for which SGLT-2 inhibitors, GLP-1 agonists, and DPP-4 inhibitors were compared with either each other or placebo or no treatment.

Data Extraction And Synthesis: Data were screened by 1 investigator and extracted in duplicate by 2 investigators. A Bayesian hierarchical network meta-analysis was performed.

Main Outcomes And Measures: The primary outcome: all-cause mortality; secondary outcomes: cardiovascular (CV) mortality, heart failure (HF) events, myocardial infarction (MI), unstable angina, and stroke; safety end points: adverse events and hypoglycemia.

Results: This network meta-analysis of 236 trials randomizing 176 310 participants found SGLT-2 inhibitors (absolute risk difference [RD], -1.0%; hazard ratio [HR], 0.80 [95% credible interval {CrI}, 0.71 to 0.89]) and GLP-1 agonists (absolute RD, -0.6%; HR, 0.88 [95% CrI, 0.81 to 0.94]) were associated with significantly lower all-cause mortality than the control groups. SGLT-2 inhibitors (absolute RD, -0.9%; HR, 0.78 [95% CrI, 0.68 to 0.90]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.86 [95% CrI, 0.77 to 0.96]) were associated with lower mortality than were DPP-4 inhibitors. DPP-4 inhibitors were not significantly associated with lower all-cause mortality (absolute RD, 0.1%; HR, 1.02 [95% CrI, 0.94 to 1.11]) than were the control groups. SGLT-2 inhibitors (absolute RD, -0.8%; HR, 0.79 [95% CrI, 0.69 to 0.91]) and GLP-1 agonists (absolute RD, -0.5%; HR, 0.85 [95% CrI, 0.77 to 0.94]) were significantly associated with lower CV mortality than were the control groups. SGLT-2 inhibitors were significantly associated with lower rates of HF events (absolute RD, -1.1%; HR, 0.62 [95% CrI, 0.54 to 0.72]) and MI (absolute RD, -0.6%; HR, 0.86 [95% CrI, 0.77 to 0.97]) than were the control groups. GLP-1 agonists were associated with a higher risk of adverse events leading to trial withdrawal than were SGLT-2 inhibitors (absolute RD, 5.8%; HR, 1.80 [95% CrI, 1.44 to 2.25]) and DPP-4 inhibitors (absolute RD, 3.1%; HR, 1.93 [95% CrI, 1.59 to 2.35]).

Conclusions And Relevance: In this network meta-analysis, the use of SGLT-2 inhibitors or GLP-1 agonists was associated with lower mortality than DPP-4 inhibitors or placebo or no treatment. Use of DPP-4 inhibitors was not associated with lower mortality than placebo or no treatment.
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http://dx.doi.org/10.1001/jama.2018.3024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5933330PMC
April 2018

Effects of disease severity distribution on the performance of quantitative diagnostic methods and proposal of a novel 'V-plot' methodology to display accuracy values.

Open Heart 2018;5(1):e000663. Epub 2018 Jan 20.

International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London and Imperial College Healthcare NHS Trust, London, UK.

Background: Diagnostic accuracy is widely accepted by researchers and clinicians as an optimal expression of a test's performance. The aim of this study was to evaluate the effects of disease severity distribution on values of diagnostic accuracy as well as propose a sample-independent methodology to calculate and display accuracy of diagnostic tests.

Methods And Findings: We evaluated the diagnostic relationship between two hypothetical methods to measure serum cholesterol (Chol and Chol) by generating samples with statistical software and (1) keeping the numerical relationship between methods unchanged and (2) changing the distribution of cholesterol values. Metrics of categorical agreement were calculated (accuracy, sensitivity and specificity). Finally, a novel methodology to display and calculate accuracy values was presented (the V-plot of accuracies).

Conclusion: No single value of diagnostic accuracy can be used to describe the relationship between tests, as accuracy is a metric heavily affected by the underlying sample distribution. Our novel proposed methodology, the V-plot of accuracies, can be used as a sample-independent measure of a test performance against a reference gold standard.
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http://dx.doi.org/10.1136/openhrt-2017-000663DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5786922PMC
January 2018

Doppler assessment of aortic stenosis: a 25-operator study demonstrating why reading the peak velocity is superior to velocity time integral.

Eur Heart J Cardiovasc Imaging 2018 12;19(12):1380-1389

Imperial College London, NHLI-Cardiovascular Science, Du Cane Road, London, UK.

Aims: Measurements with superior reproducibility are useful clinically and research purposes. Previous reproducibility studies of Doppler assessment of aortic stenosis (AS) have compared only a pair of observers and have not explored the mechanism by which disagreement between operators occurs. Using custom-designed software which stored operators' traces, we investigated the reproducibility of peak and velocity time integral (VTI) measurements across a much larger group of operators and explored the mechanisms by which disagreement arose.

Methods And Results: Twenty-five observers reviewed continuous wave (CW) aortic valve (AV) and pulsed wave (PW) left ventricular outflow tract (LVOT) Doppler traces from 20 sequential cases of AS in random order. Each operator unknowingly measured each peak velocity and VTI twice. VTI tracings were stored for comparison. Measuring the peak is much more reproducible than VTI for both PW (coefficient of variation 10.1 vs. 18.0%; P < 0.001) and CW traces (coefficient of variation 4.0 vs. 10.2%; P < 0.001). VTI is inferior because the steep early and late parts of the envelope are difficult to trace reproducibly. Dimensionless index improves reproducibility because operators tended to consistently over-read or under-read on LVOT and AV traces from the same patient (coefficient of variation 9.3 vs. 17.1%; P < 0.001).

Conclusion: It is far more reproducible to measure the peak of a Doppler trace than the VTI, a strategy that reduces measurement variance by approximately six-fold. Peak measurements are superior to VTI because tracing the steep slopes in the early and late part of the VTI envelope is difficult to achieve reproducibly.
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http://dx.doi.org/10.1093/ehjci/jex218DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6247666PMC
December 2018

Fractional Flow Reserve/Instantaneous Wave-Free Ratio Discordance in Angiographically Intermediate Coronary Stenoses: An Analysis Using Doppler-Derived Coronary Flow Measurements.

JACC Cardiovasc Interv 2017 12;10(24):2514-2524

Imperial College London, London, United Kingdom. Electronic address:

Objectives: The study sought to determine the coronary flow characteristics of angiographically intermediate stenoses classified as discordant by fractional flow reserve (FFR) and instantaneous wave-free ratio (iFR).

Background: Discordance between FFR and iFR occurs in up to 20% of cases. No comparisons have been reported between the coronary flow characteristics of FFR/iFR discordant and angiographically unobstructed vessels.

Methods: Baseline and hyperemic coronary flow velocity and coronary flow reserve (CFR) were compared across 5 vessel groups: FFR+/iFR+ (108 vessels, n = 91), FFR-/iFR+ (28 vessels, n = 24), FFR+/iFR- (22 vessels, n = 22), FFR-/iFR- (208 vessels, n = 154), and an unobstructed vessel group (201 vessels, n = 153), in a post hoc analysis of the largest combined pressure and Doppler flow velocity registry (IDEAL [Iberian-Dutch-English] collaborators study).

Results: FFR disagreed with iFR in 14% (50 of 366). Baseline flow velocity was similar across all 5 vessel groups, including the unobstructed vessel group (p = 0.34 for variance). In FFR+/iFR- discordants, hyperemic flow velocity and CFR were similar to both FFR-/iFR- and unobstructed groups; 37.6 (interquartile range [IQR]: 26.1 to 50.4) cm/s vs. 40.0 [IQR: 29.7 to 52.3] cm/s and 42.2 [IQR: 33.8 to 53.2] cm/s and CFR 2.36 [IQR: 1.93 to 2.81] vs. 2.41 [IQR: 1.84 to 2.94] and 2.50 [IQR: 2.11 to 3.17], respectively (p > 0.05 for all). In FFR-/iFR+ discordants, hyperemic flow velocity, and CFR were similar to the FFR+/iFR+ group; 28.2 (IQR: 20.5 to 39.7) cm/s versus 23.5 (IQR: 16.4 to 34.9) cm/s and CFR 1.44 (IQR: 1.29 to 1.85) versus 1.39 (IQR: 1.06 to 1.88), respectively (p > 0.05 for all).

Conclusions: FFR/iFR disagreement was explained by differences in hyperemic coronary flow velocity. Furthermore, coronary stenoses classified as FFR+/iFR- demonstrated similar coronary flow characteristics to angiographically unobstructed vessels.
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http://dx.doi.org/10.1016/j.jcin.2017.09.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5743106PMC
December 2017