Publications by authors named "Zachary I Whinnett"

75 Publications

Novel Low-Voltage MultiPulse Therapy to Terminate Atrial Fibrillation.

JACC Clin Electrophysiol 2021 Mar 25. Epub 2021 Mar 25.

George Washington University, Washington, DC, USA. Electronic address:

Objectives: This first-in-human feasibility study was undertaken to translate the novel low-voltage MultiPulse Therapy (MPT) (Cardialen, Inc., Minneapolis, Minnesota), which was previously been shown to be effective in preclinical studies in terminating atrial fibrillation (AF), into clinical use.

Background: Current treatment options for AF, the most common arrhythmia in clinical practice, have limited success. Previous attempts at treating AF by using implantable devices have been limited by the painful nature of high-voltage shocks.

Methods: Forty-two patients undergoing AF ablation were recruited at 6 investigational centers worldwide. Before ablation, electrode catheters were placed in the coronary sinus, right and/or left atrium, for recording and stimulation. After the induction of AF, MPT, which consists of up to a 3-stage sequence of far- and near-field stimulation pulses of varied amplitude, duration, and interpulse timing, was delivered via temporary intracardiac leads. MPT parameters and delivery methods were iteratively optimized.

Results: In the 14 patients from the efficacy phase, MPT terminated 37 of 52 (71%) of AF episodes, with the lowest median energy of 0.36 J (interquartile range: 0.14 to 1.21 J) and voltage of 42.5 V (interquartile range: 25 to 75 V). Overall, 38% of AF terminations occurred within 2 seconds of MPT delivery (p < 0.0001). Shorter time between AF induction and MPT predicted success of MPT in terminating AF (p < 0.001).

Conclusions: MPT effectively terminated AF at voltages and energies known to be well tolerated or painless in some patients. Our results support further studies of the concept of implanted devices for early AF conversion to reduce AF burden, symptoms, and progression.
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http://dx.doi.org/10.1016/j.jacep.2020.12.014DOI Listing
March 2021

Long-Term Safety and Feasibility of Left Bundle Branch Pacing in a Large Single-Center Study.

Circ Arrhythm Electrophysiol 2021 Feb 9;14(2):e009261. Epub 2021 Jan 9.

Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, China (L.S., S. Wang, S. Wu, L.X., Z.H., X.C., R.Z., L.J., W.H.).

Background: Left bundle branch pacing (LBBP) is a novel pacing method and has been observed to have low and stable pacing thresholds in prior small short-term studies. The objective of this study was to evaluate the feasibility and safety of LBBP in a large consecutive diverse group of patients with long-term follow-up.

Methods: This study prospectively enrolled 632 consecutive pacemaker patients with attempted LBBP from April 2017 to July 2019. Pacing parameters, complications, ECG, and echocardiographic measurements were assessed at implant and during follow-up of 1, 6, 12, and 24 months.

Results: LBBP was successful in 618/632 (97.8%) patients according to strict criteria for LBB capture. Mean follow-up time was 18.6±6.7 months. Two hundred thirty-one patients had follow-up over 2 years. LBB capture threshold at implant was 0.65±0.27 mV at 0.5 ms and 0.69±0.24 mV at 0.5 ms at 2-year follow-up. A significant decrease in QRS duration was observed in patients with left bundle branch block (167.22±18.99 versus 124.02±24.15 ms, <0.001). Postimplantation left ventricular ejection fraction improved in patients with QRS≥120 ms (48.82±17.78% versus 58.12±13.04%, <0.001). The number of patients with moderate and severe tricuspid regurgitation decreased at 1 year. Permanent right bundle branch injury occurred in 55 (8.9%) patients. LBB capture threshold increased to >3 V or loss of bundle capture in 6 patients (1%), 2 patients of them had a loss of conduction system capture. Two patients required lead revision due to dislodgement.

Conclusions: This large observational study suggests that LBBP is feasible with high success rates and low complication rates during long-term follow-up. Therefore, LBBP appears to be a reliable method for physiological pacing for patients with either a bradycardia or heart failure pacing indication.
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http://dx.doi.org/10.1161/CIRCEP.120.009261DOI Listing
February 2021

Targeting the ectopy-triggering ganglionated plexuses without pulmonary vein isolation prevents atrial fibrillation.

J Cardiovasc Electrophysiol 2021 Feb 19;32(2):235-244. Epub 2021 Jan 19.

Myocardial Function Section, National Heart and Lung Institute, Imperial College London, London, UK.

Background: Ganglionated plexuses (GPs) are implicated in atrial fibrillation (AF). Endocardial high-frequency stimulation (HFS) delivered within the local atrial refractory period can trigger ectopy and AF from specific GP sites (ET-GP). The aim of this study was to understand the role of ET-GP ablation in the treatment of AF.

Methods: Patients with paroxysmal AF indicated for ablation were recruited. HFS mapping was performed globally around the left atrium to identify ET-GP. ET-GP was defined as atrial ectopy or atrial arrhythmia triggered by HFS. All ET-GP were ablated, and PVs were left electrically connected. Outcomes were compared with a control group receiving pulmonary vein isolation (PVI). Patients were followed-up for 12 months with multiple 48-h Holter ECGs. Primary endpoint was ≥30 s AF/atrial tachycardia in ECGs.

Results: In total, 67 patients were recruited and randomized to ET-GP ablation (n = 39) or PVI (n = 28). In the ET-GP ablation group, 103 ± 28 HFS sites were tested per patient, identifying 21 ± 10 (20%) GPs. ET-GP ablation used 23.3 ± 4.1 kWs total radiofrequency (RF) energy per patient, compared with 55.7 ± 22.7 kWs in PVI (p = <.0001). Duration of procedure was 3.7 ± 1.0 and 3.3 ± 0.7 h in ET-GP ablation group and PVI, respectively (p = .07). Follow-up at 12 months showed that 61% and 49% were free from ≥30 s of AF/AT with PVI and ET-GP ablation respectively (log-rank p = .27).

Conclusions: It is feasible to perform detailed global functional mapping with HFS and ablate ET-GP to prevent AF. This provides direct evidence that ET-GPs are part of the AF mechanism. The lower RF requirement implies that ET-GP targets the AF pathway more specifically.
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http://dx.doi.org/10.1111/jce.14870DOI Listing
February 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

His-Purkinje Conduction System Pacing: State of the Art in 2020.

Arrhythm Electrophysiol Rev 2020 Nov;9(3):136-145

Geisinger Heart Institute, Geisinger Commonwealth School of Medicine, Wilkes-Barre, Pennsylvania, US.

Conduction system pacing involves directly stimulating the specialised His-Purkinje cardiac conduction system with the aim of activating the ventricles physiologically, in contrast to the dyssynchronous activation produced by conventional myocardial pacing. Since the first report of permanent His bundle pacing (HBP) in 2000, the stylet-driven technique of its earliest incarnation has been superseded by a more successful stylet-less approach. Widespread uptake has led to a much greater evidence base. Single-centre observational studies have now been supported by large multicentre, international registries, mechanistic studies and the first randomised controlled trials. New evidence has elucidated mechanisms of HBP and illustrated the nature and magnitude of its potential benefits for preventing pacing-induced cardiomyopathy and correcting bundle branch block. Left bundle branch pacing (LBBP) is a newer technique in which the lead is fixed deep into the left side of the intraventricular septum to allow capture of the left bundle, distal to the His bundle. LBBP holds promise as a method for physiological pacing that overcomes some of the fixation, threshold and sensing challenges of HBP. In this state-of-the-art review of His-Purkinje conduction system pacing, the authors assess recent evidence and current practice and explore emerging and future directions in this rapidly evolving field.
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http://dx.doi.org/10.15420/aer.2020.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7675135PMC
November 2020

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

The ectopy-triggering ganglionated plexuses in atrial fibrillation.

Auton Neurosci 2020 11 21;228:102699. Epub 2020 Jul 21.

Myocardial Function Section, NHLI, Imperial College London, UK; Department of Cardiology, Imperial College Healthcare NHS Trust, London, UK; Imperial Centre for Cardiac Engineering, Imperial College London, London, UK. Electronic address:

Background: Epicardial ganglionated plexuses (GP) have an important role in the pathogenesis of atrial fibrillation (AF). The relationship between anatomical, histological and functional effects of GP is not well known. We previously described atrioventricular (AV) dissociating GP (AVD-GP) locations. In this study, we hypothesised that ectopy triggering GP (ET-GP) are upstream triggers of atrial ectopy/AF and have different anatomical distribution to AVD-GP.

Objectives: We mapped and characterised ET-GP to understand their neural mechanism in AF and anatomical distribution in the left atrium (LA).

Methods: 26 patients with paroxysmal AF were recruited. All were paced in the LA with an ablation catheter. High frequency stimulation (HFS) was synchronised to each paced stimulus for delivery within the local atrial refractory period. HFS responses were tagged onto CARTO™ 3D LA geometry. All geometries were transformed onto one reference LA shell. A probability distribution atlas of ET-GP was created. This identified high/low ET-GP probability regions.

Results: 2302 sites were tested with HFS, identifying 579 (25%) ET-GP. 464 ET-GP were characterised, where 74 (16%) triggered ≥30s AF/AT. Median 97 (IQR 55) sites were tested, identifying 19 (20%) ET-GP per patient. >30% of ET-GP were in the roof, mid-anterior wall, around all PV ostia except in the right inferior PV (RIPV) in the posterior wall.

Conclusion: ET-GP can be identified by endocardial stimulation and their anatomical distribution, in contrast to AVD-GP, would be more likely to be affected by wide antral circumferential ablation. This may contribute to AF ablation outcomes.
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http://dx.doi.org/10.1016/j.autneu.2020.102699DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7511599PMC
November 2020

Anatomical Distribution of Ectopy-Triggering Plexuses in Patients With Atrial Fibrillation.

Circ Arrhythm Electrophysiol 2020 09 27;13(9):e008715. Epub 2020 Jul 27.

Myocardial Function Section, Imperial Centre for Translational and Experimental Medicine (M.-Y.K., B.C.S., M.B.S., C.D.C., F.S.N., N.S.P., P.B.L., N.W.F.L., P.K.), Imperial College London, United Kingdom.

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http://dx.doi.org/10.1161/CIRCEP.120.008715DOI Listing
September 2020

Cardiac Resynchronization Therapy in Patients With Nonischemic Cardiomyopathy Using Left Bundle Branch Pacing.

JACC Clin Electrophysiol 2020 07;6(7):849-858

University of Chicago Medicine, Center for Arrhythmia Care, Pritzker School of Medicine, Department of Medicine, Section of Cardiology, Chicago, Illinois, USA.

Objectives: The aim of this study was to assess the feasibility and efficacy of left bundle branch pacing (LBBP) using a novel intraseptal technique to deliver cardiac resynchronization therapy (CRT) in patients with left bundle branch block (LBBB) and nonischemic cardiomyopathy.

Background: His bundle pacing to correct LBBB is a viable alternative approach to achieve CRT but is limited by suboptimal lead delivery and high thresholds.

Methods: This was a prospective, multicenter study performed between June 2017 and August 2018 at 6 centers. Patients with nonischemic cardiomyopathy, complete LBBB, and left ventricular ejection fractions (LVEFs) ≤50% who had indications for CRT and/or ventricular pacing in whom LBBP was attempted were included. Success rates, QRS duration, LVEF, left ventricular end-systolic volume, and improvement in functional class were assessed.

Results: LBBP was successful in 61 of 63 patients (97%, mean age 68 ± 11 years, 52.4% men). During LBBP, QRS duration narrowed from 169 ± 16 to 118 ± 12 ms (p < 0.001). Pacing threshold and R-wave amplitude remained stable at 1-year follow-up compared with implantation values (0.5 ± 0.15 V/0.5 ms vs. 0.58 ± 0.14 V/0.5 ms and 11.1 ± 4.9 mV vs. 13.3 ± 5.3 mV, respectively). LVEF increased significantly (33 ± 8% vs. 55 ± 10%; p < 0.001), with a reduction in left ventricular end-systolic volume (123 ± 61 ml vs. 67 ± 39 ml; p < 0.001). LVEF had normalized (≥50%) in 75% of patients at 1 year. New York Heart Association functional class improved significantly from 2.8 ± 0.6 at baseline to 1.4 ± 0.6 at 1 year. No deaths or heart failure hospitalizations were observed during follow-up.

Conclusions: LBBP is a feasible and effective method for achieving electric resynchronization of LBBB, with resultant improvements in left ventricular structure and function. Low and stable pacing thresholds may be advantageous over His bundle pacing for CRT in patients with LBBB and nonischemic cardiomyopathy.
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http://dx.doi.org/10.1016/j.jacep.2020.04.011DOI Listing
July 2020

Artificial Intelligence, Data Sensors and Interconnectivity: Future Opportunities for Heart Failure.

Card Fail Rev 2020 Mar 12;6:e11. Epub 2020 May 12.

Imperial Centre for Cardiac Engineering, National Heart and Lung Institute, Imperial College London, UK.

A higher proportion of patients with heart failure have benefitted from a wide and expanding variety of sensor-enabled implantable devices than any other patient group. These patients can now also take advantage of the ever-increasing availability and affordability of consumer electronics. Wearable, on- and near-body sensor technologies, much like implantable devices, generate massive amounts of data. The connectivity of all these devices has created opportunities for pooling data from multiple sensors - so-called interconnectivity - and for artificial intelligence to provide new diagnostic, triage, risk-stratification and disease management insights for the delivery of better, more personalised and cost-effective healthcare. Artificial intelligence is also bringing important and previously inaccessible insights from our conventional cardiac investigations. The aim of this article is to review the convergence of artificial intelligence, sensor technologies and interconnectivity and the way in which this combination is set to change the care of patients with heart failure.
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http://dx.doi.org/10.15420/cfr.2019.14DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7265101PMC
March 2020

Left Bundle Branch Pacing for Cardiac Resynchronization Therapy: Nonrandomized On-Treatment Comparison With His Bundle Pacing and Biventricular Pacing.

Can J Cardiol 2021 Feb 7;37(2):319-328. Epub 2020 May 7.

Department of Cardiology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou, China; The Key Lab of Cardiovascular Disease of Wenzhou, Wenzhou, China. Electronic address:

Background: Left bundle branch pacing (LBBP) is a novel method for delivering cardiac resynchronization therapy (CRT). We compared on-treatment outcomes with His bundle pacing (HBP) and biventricular pacing (BVP) in this nonrandomized observational study.

Methods: Consecutive patients with left-ventricular ejection fraction (LVEF) ≤ 40% and typical left bundle branch block (LBBB) referred for CRT received BVP, HBP, or LBBP. QRS duration, pacing threshold, LVEF, and New York Heart Association (NYHA) class were assessed.

Results: One hundred thirty-seven patients were recruited: 49 HBP, 32 LBBP, and 54 BVP; 2 did not receive CRT. The majority of patients had nonischemic cardiomyopathy. Mean paced QRS duration was 100.7 ± 15.3 ms, 110.8 ± 11.1 ms, and 135.4 ± 20.2 ms during HBP, LBBP, and BVP, respectively. HBP and LBBP demonstrated a similar absolute increase (Δ) in LVEF (+23.9% vs +24%, P = 0.977) and rate of normalized final LVEF (74.4% vs 70.0%, P = 0.881) at 1-year follow-up. This was significantly higher than in the BVP group (Δ LVEF +16.7% and 44.9% rate of normalized final LVEF, P < 0.005). HBP and LBBP also demonstrated greater improvements in NYHA class compared with BVP. LBBP was associated with higher R-wave amplitude (11.2 ± 5.1 mV vs 3.8 ± 1.9 mV, P < 0.001) and lower pacing threshold (0.49 ± 0.13 V/0.5 ms vs 1.35 ± 0.73 V/0.5 ms, P < 0.001) compared with HBP.

Conclusion: LBBP appears to be a promising method for delivering CRT. We observed similar improvements in symptoms and LV function with LBBP and HBP. These improvements were significantly greater than those seen in patients treated with BVP in this nonrandomized study. These promising findings justify further investigation with randomized trials.
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http://dx.doi.org/10.1016/j.cjca.2020.04.037DOI Listing
February 2021

Granger Causality-Based Analysis for Classification of Fibrillation Mechanisms and Localization of Rotational Drivers.

Circ Arrhythm Electrophysiol 2020 03 16;13(3):e008237. Epub 2020 Feb 16.

National Heart & Lung Institute, Imperial College London, United Kingdom (B.S.H., X.L., N.A.Q., I.M., R.A.C., Z.I.W., N.W.F.L., P.B.L., P.K., N.S.P., F.S.N.).

Background: The mechanisms sustaining myocardial fibrillation remain disputed, partly due to a lack of mapping tools that can accurately identify the mechanism with low spatial resolution clinical recordings. Granger causality (GC) analysis, an econometric tool for quantifying causal relationships between complex time-series, was developed as a novel fibrillation mapping tool and adapted to low spatial resolution sequentially acquired data.

Methods: Ventricular fibrillation (VF) optical mapping was performed in Langendorff-perfused Sprague-Dawley rat hearts (n=18), where novel algorithms were developed using GC-based analysis to (1) quantify causal dependence of neighboring signals and plot GC vectors, (2) quantify global organization with the causality pairing index, a measure of neighboring causal signal pairs, and (3) localize rotational drivers (RDs) by quantifying the circular interdependence of neighboring signals with the circular interdependence value. GC-based mapping tools were optimized for low spatial resolution from downsampled optical mapping data, validated against high-resolution phase analysis and further tested in previous VF optical mapping recordings of coronary perfused donor heart left ventricular wedge preparations (n=12), and adapted for sequentially acquired intracardiac electrograms during human persistent atrial fibrillation mapping (n=16).

Results: Global VF organization quantified by causality pairing index showed a negative correlation at progressively lower resolutions (50% resolution: =0.006, =0.38, 12.5% resolution, =0.004, =0.41) with a phase analysis derived measure of disorganization, locations occupied by phase singularities. In organized VF with high causality pairing index values, GC vector mapping characterized dominant propagating patterns and localized stable RDs, with the circular interdependence value showing a significant difference in driver versus nondriver regions (0.91±0.05 versus 0.35±0.06, =0.0002). These findings were further confirmed in human VF. In persistent atrial fibrillation, a positive correlation was found between the causality pairing index and presence of stable RDs (=0.0005,=0.56). Fifty percent of patients had RDs, with a low incidence of 0.9±0.3 RDs per patient.

Conclusions: GC-based fibrillation analysis can measure global fibrillation organization, characterize dominant propagating patterns, and map RDs using low spatial resolution sequentially acquired data.
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http://dx.doi.org/10.1161/CIRCEP.119.008237DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069398PMC
March 2020

Feasibility and Efficacy of His Bundle Pacing or Left Bundle Pacing Combined With Atrioventricular Node Ablation in Patients With Persistent Atrial Fibrillation and Implantable Cardioverter-Defibrillator Therapy.

J Am Heart Assoc 2019 12 13;8(24):e014253. Epub 2019 Dec 13.

Department of Cardiology the First Affiliated Hospital of Wenzhou Medical University Wenzhou China.

Background Persistent atrial fibrillation may lead to a higher probability of inappropriate shocks in heart failure patients with an implantable cardioverter-defibrillator (ICD). The aim of this study was to evaluate the impact of His-Purkinje conduction system pacing combined with atrioventricular node ablation in improving heart function and preventing inappropriate shock therapy in these patients. Methods and Results A total of 86 consecutive patients with persistent atrial fibrillation and heart failure who had indications for ICD implantation were enrolled from January 2010 to March 2018. His-Purkinje conduction system pacing with ICD and atrioventricular node ablation was attempted in 55 patients, and the remaining patients underwent ICD implantation only. Left ventricular (LV) ejection fraction, LV end-systolic volume, New York Heart Association (NYHA) classification, shock therapies, and drug therapy were assessed during follow-up. Overall, 31 patients received ICD implantation with optimal drug therapy (group 1). atrioventricular node ablation combined with His-Purkinje conduction system pacing was successfully achieved in 52 patients (group 2). During follow-up, patients in group 2 had lower incidence of inappropriate shock (15.6% versus 0%, <0.01) and adverse events (=0.011). Meanwhile, improvement in LV ejection fraction and reduction in LV end-systolic volume were significantly higher in group 2 than in group 1 (15% versus 3%, <0.001; and 40 versus 2 mL, <0.01, respectively). NYHA functional class improved in both groups from a baseline 2.57±0.68 to 1.73±0.74 in group 1 and 2.73±0.59 to 1.42±0.53 in group 2 (<0.01). Conclusions His-Purkinje conduction system pacing combined with atrioventricular node ablation is feasible and safe with a high success rate in persistent atrial fibrillation patients with heart failure and ICD indication. It can significantly reduce the incidence of inappropriate shocks and improve LV function.
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http://dx.doi.org/10.1161/JAHA.119.014253DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6951078PMC
December 2019

Meta-Analysis of Randomized Controlled Trials of Atrial Fibrillation Ablation With Pulmonary Vein Isolation Versus Without.

JACC Clin Electrophysiol 2019 08 31;5(8):968-976. Epub 2019 Jul 31.

National Heart and Lung Institute, Imperial College London, London, United Kingdom; Department of Cardiac Electrophysiology, Bart's Heart Centre, St Bartholomew's Hospital, London, United Kingdom; Department of Cardiology, King George Hospital, Ilford, United Kingdom. Electronic address:

Objectives: This meta-analysis examined the ability of pulmonary vein isolation (PVI) to prevent atrial fibrillation in randomized controlled trials (RCTs) in which the patients not receiving PVI nevertheless underwent a procedure.

Background: PVI is a commonly used procedure for the treatment of atrial fibrillation (AF), and its efficacy has usually been judged against therapy with anti-arrhythmic drugs in open-label trials. There have been several RCTs of AF ablation in which both arms received an ablation, but the difference between the treatment arms was inclusion or omission of PVI. These trials of an ablation strategy with PVI versus an ablation strategy without PVI may provide a more rigorous method for evaluating the efficacy of PVI.

Methods: Medline and Cochrane databases were searched for RCTs comparing ablation including PVI with ablation excluding PVI. The primary efficacy endpoint was freedom from atrial fibrillation (AF) and atrial tachycardia at 12 months. A random-effects meta-analysis was performed using the restricted maximum likelihood estimator.

Results: Overall, 6 studies (n = 610) met inclusion criteria. AF recurrence was significantly lower with an ablation including PVI than an ablation without PVI (RR: 0.54; 95% confidence interval [CI]: 0.33 to 0.89; p = 0.0147; I = 79.7%). Neither the type of AF (p = 0.48) nor the type of non-PVI ablation (p = 0.21) was a significant moderator of the effect size. In 3 trials the non-PVI ablation procedure was performed in both arms, whereas PVI was performed in only 1 arm. In these studies, AF recurrence was significantly lower when PVI was included (RR: 0.32; 95% CI: 0.14 to 0.73; p = 0.007, I 78%).

Conclusions: In RCTs where both arms received an ablation, and therefore an expectation amongst patients and doctors of benefit, being randomized to PVI had a striking effect, reducing AF recurrence by a half.
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http://dx.doi.org/10.1016/j.jacep.2019.05.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6709782PMC
August 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

Voltage during atrial fibrillation is superior to voltage during sinus rhythm in localizing areas of delayed enhancement on magnetic resonance imaging: An assessment of the posterior left atrium in patients with persistent atrial fibrillation.

Heart Rhythm 2019 09 3;16(9):1357-1367. Epub 2019 Jun 3.

Imperial College Healthcare NHS Trust, Hammersmith Hospital, London, United Kingdom. Electronic address:

Background: Bipolar electrogram voltage during sinus rhythm (V) has been used as a surrogate for atrial fibrosis in guiding catheter ablation of persistent atrial fibrillation (AF), but the fixed rate and wavefront characteristics present during sinus rhythm may not accurately reflect underlying functional vulnerabilities responsible for AF maintenance.

Objective: The purpose of this study was determine whether, given adequate temporal sampling, the spatial distribution of mean AF voltage (V) better correlates with delayed-enhancement magnetic resonance imaging (MRI-DE)-detected atrial fibrosis than V.

Methods: AF was mapped (8 seconds) during index ablation for persistent AF (20 patients) using a 20-pole catheter (660 ± 28 points/map). After cardioversion, V was mapped (557 ± 326 points/map). Electroanatomic and MRI-DE maps were co-registered in 14 patients.

Results: The time course of V was assessed from 1-40 AF cycles (∼8 seconds) at 1113 locations. V stabilized with sampling >4 seconds (mean voltage error 0.05 mV). Paired point analysis of V from segments acquired 30 seconds apart (3667 sites; 15 patients) showed strong correlation (r = 0.95; P <.001). Delayed enhancement (DE) was assessed across the posterior left atrial (LA) wall, occupying 33% ± 13%. V distributions were (median [IQR]) 0.21 [0.14-0.35] mV in DE vs 0.52 [0.34-0.77] mV in non-DE regions. V distributions were 1.34 [0.65-2.48] mV in DE vs 2.37 [1.27-3.97] mV in non-DE. V threshold of 0.35 mV yielded sensitivity of 75% and specificity of 79% in detecting MRI-DE compared with 63% and 67%, respectively, for V (1.8-mV threshold) CONCLUSION: The correlation between low-voltage and posterior LA MRI-DE is significantly improved when acquired during AF vs sinus rhythm. With adequate sampling, mean AF voltage is a reproducible marker reflecting the functional response to the underlying persistent AF substrate.
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http://dx.doi.org/10.1016/j.hrthm.2019.05.032DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6722483PMC
September 2019

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

Prevalence of spontaneous type I ECG pattern, syncope, and other risk markers in sudden cardiac arrest survivors with Brugada syndrome.

Pacing Clin Electrophysiol 2019 02 6;42(2):257-264. Epub 2019 Jan 6.

Imperial College Healthcare NHS Trust, London, UK.

Introduction: A spontaneous type I electrocardiogram (ECG) pattern and/or unheralded syncope are conventionally used as risk markers for primary prevention of sudden cardiac arrest/death (SCA/SCD) in Brugada syndrome (BrS). In this study, we determine the prevalence of conventional and newer markers of risk in those with and without previous aborted SCA events.

Methods: All patients with BrS were identified at our institute. History of symptoms was obtained from medical tests or from interviews. Other markers of risk were also obtained, such as presence of (1) spontaneous type I pattern, (2) fractionated QRS (fQRS), (3) early repolarization (ER) pattern, (4) late potentials on signal-averaged ECG (SAECG), and (5) response to programmed electrical stimulation.

Results: In 133 patients with Bars, 10 (7%) patients (mean age = 39 ± 11 years; nine males) were identified with a previous ventricular fibrillation/ventricular tachycardia episode (n = 8) or requiring cardio-pulmonary resuscitation (n = 2). None of these patients had a prior history of syncope before their SCA event. Only two (20%) patients reported a history of palpitations or dizziness. None had apneic breathing and three (30%) patients had a family history of SCA. From their ECGs, a spontaneous pattern was only found in one (10%) of these patients. Further, 10% of patients had fQRS, 17% had late potentials on SAECG, 20% had deep S waves in lead I, and 10% had an ER pattern in the peripheral leads. No significant differences were observed in the non-SCA group.

Conclusion: The majority of BrS patients with previous aborted SCA events did not have a spontaneous type I and/or prior history of syncope. Conventional and newer markers of risk appear to only have limited ability to predict SCA.
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http://dx.doi.org/10.1111/pace.13587DOI Listing
February 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

Permanent His Bundle Pacing for Cardiac Resynchronization Therapy in Patients With Heart Failure and Right Bundle Branch Block.

Circ Arrhythm Electrophysiol 2018 09;11(9):e006613

Geisinger Heart Institute, Wilkes-Barre, PA (A.N., T.D.B., P.V.).

Background Cardiac resynchronization therapy utilizing biventricular pacing is an effective therapy for patients with left ventricular (LV) systolic dysfunction, left bundle branch block, and heart failure. Benefits of biventricular pacing may be limited in patients with right bundle branch block (RBBB). Permanent His bundle pacing (HBP) has recently been reported as an option for cardiac resynchronization therapy. The aim of the study was to assess the feasibility and outcomes of HBP in patients with RBBB and heart failure. Methods HBP was attempted as a primary or rescue (failed LV lead implant) strategy in patients with reduced LV ejection fraction, RBBB, QRS duration ≥120 ms, and New York Heart Association class II to IV heart failure. Implant characteristics, New York Heart Association functional class, and echocardiographic data were assessed in follow-up. Results Mean age was 72±10 years, female 15%, with an average LV ejection fraction of 31±10%. HBP was successful in 37 of 39 patients (95%) with narrowing of RBBB in 78% cases. His capture and bundle branch block correction thresholds were 1.1±0.6 V and 1.4±0.7 V at 1 ms, respectively. During a mean follow-up of 15±23 months, there was a significant narrowing of QRS from 158±24 to 127±17 ms ( P=0.0001), increase in LV ejection fraction from 31±10% to 39±13% ( P=0.004), and improvement in New York Heart Association functional class from 2.8±0.6 to 2±0.7 ( P=0.0001) with HBP. Increase in capture threshold occurred in 3 patients. Conclusions Permanent HBP was associated with significant narrowing of QRS duration and improvement in LV function in patients with RBBB and reduced LV ejection fraction. Permanent HBP is a promising option for cardiac resynchronization therapy in patients with RBBB and reduced LV ejection fraction.
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http://dx.doi.org/10.1161/CIRCEP.118.006613DOI Listing
September 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

His Bundle Pacing: A New Frontier in the Treatment of Heart Failure.

Arrhythm Electrophysiol Rev 2018 Jun;7(2):103-110

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

Biventricular pacing has revolutionised the treatment of heart failure in patients with sinus rhythm and left bundle branch block; however, left ventricular-lead placement is not always technically possible. Furthermore, biventricular pacing does not fully normalise ventricular activation and, therefore, the ventricular resynchronisation is imperfect. Right ventricular pacing for bradycardia may cause or worsen heart failure in some patients by causing dyssynchronous ventricular activation. His bundle pacing activates the ventricles via the native His-Purkinje system, resulting in true physiological pacing, and, therefore, is a promising alternate site for pacing in bradycardia and traditional CRT indications in cases where it can overcome left bundle branch block. Furthermore, it may open up new indications for pacing therapy in heart failure, such as targeting patients with PR prolongation, but a narrow QRS duration. In this article we explore the physiology, technology and potential roles of His bundle pacing in the prevention and treatment of heart failure.
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http://dx.doi.org/10.15420/aer.2018.6.2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6020230PMC
June 2018

Distinct impacts of heart rate and right atrial-pacing on left atrial mechanical activation and optimal AV delay in CRT.

Pacing Clin Electrophysiol 2018 Jun 1. Epub 2018 Jun 1.

International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, W12 0HS, UK.

Background: Controversy exists regarding how atrial activation mode and heart rate affect optimal atrioventricular (AV) delay in cardiac resynchronization therapy. We studied these questions using high-reproducibility hemodynamic and echocardiographic measurements.

Methods: Twenty patients were hemodynamically optimized using noninvasive beat-to-beat blood pressure at rest (62 ± 11 beats/min), during exercise (80 ± 6 beats/min), and at three atrially paced rates: 5, 25, and 45 beats/min above rest, denoted as A , A , and A , respectively. Left atrial myocardial motion and transmitral flow were timed echocardiographically.

Results: During atrial sensing, raising heart rate shortened optimal AV delay by 25 ± 6 ms (P < 0.001). During atrial pacing, raising heart rate from A to A shortened it by 16 ± 6 ms; A shortened it 17 ± 6 ms further (P < 0.001). In comparison to atrial-sensed activation, atrial pacing lengthened optimal AV delay by 76 ± 6 ms (P < 0.0001) at rest, and at ∼20 beats/min faster, by 85 ± 7 ms (P < 0.0001), 9 ± 4 ms more (P  =  0.017). Mechanically, atrial pacing delayed left atrial contraction by 63 ± 5 ms at rest and by 73 ± 5 ms (i.e., by 10 ± 5 ms more, P < 0.05) at ∼20 beats/min faster. Raising atrial rate by exercise advanced left atrial contraction by 7 ± 2 ms (P  =  0.001). Raising it by atrial pacing did not (P  =  0.2).

Conclusions: Hemodynamic optimal AV delay shortens with elevation of heart rate. It lengthens on switching from atrial-sensed to atrial-paced at the same rate, and echocardiography shows this sensed-paced difference in optima results from a sensed-paced difference in atrial electromechanical delay. The reason for the widening of the sensed-paced difference in AV optimum may be physiological stimuli (e.g., adrenergic drive) advancing left atrial contraction during exercise but not with fast atrial pacing.
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http://dx.doi.org/10.1111/pace.13401DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6099378PMC
June 2018

Multicenter Randomized Controlled Crossover Trial Comparing Hemodynamic Optimization Against Echocardiographic Optimization of AV and VV Delay of Cardiac Resynchronization Therapy: The BRAVO Trial.

JACC Cardiovasc Imaging 2019 08 16;12(8 Pt 1):1407-1416. Epub 2018 May 16.

Department of Cardiology, International Centre for Circulatory Health, National Heart and Lung Institute, Imperial College London, London, United Kingdom. Electronic address:

Objectives: BRAVO (British Randomized Controlled Trial of AV and VV Optimization) is a multicenter, randomized, crossover, noninferiority trial comparing echocardiographic optimization of atrioventricular (AV) and interventricular delay with a noninvasive blood pressure method.

Background: Cardiac resynchronization therapy including AV delay optimization confers clinical benefit, but the optimization requires time and expertise to perform.

Methods: This study randomized patients to echocardiographic optimization or hemodynamic optimization using multiple-replicate beat-by-beat noninvasive blood pressure at baseline; after 6 months, participants were crossed over to the other optimization arm of the trial. The primary outcome was exercise capacity, quantified as peak exercise oxygen uptake. Secondary outcome measures were echocardiographic left ventricular (LV) remodeling, quality-of-life scores, and N-terminal pro-B-type natriuretic peptide.

Results: A total of 401 patients were enrolled, the median age was 69 years, 78% of patients were men, and the New York Heart Association functional class was II in 84% and III in 16%. The primary endpoint, peak oxygen uptake, met the criterion for noninferiority (p = 0.0001), with no significant difference between the hemodynamically optimized arm and echocardiographically optimized arm of the trial (mean difference 0.1 ml/kg/min). Secondary endpoints for noninferiority were also met for symptoms (mean difference in Minnesota score 1; p = 0.002) and hormonal changes (mean change in N-terminal pro-B-type natriuretic peptide -10 pg/ml; p = 0.002). There was no significant difference in LV size (mean change in LV systolic dimension 1 mm; p < 0.001; LV diastolic dimension 0 mm; p <0.001). In 30% of patients the AV delay identified as optimal was more than 20 ms from the nominal setting of 120 ms.

Conclusions: Optimization of cardiac resynchronization therapy devices by using noninvasive blood pressure is noninferior to echocardiographic optimization. Therefore, noninvasive hemodynamic optimization is an acceptable alternative that has the potential to be automated and thus more easily implemented. (British Randomized Controlled Trial of AV and VV Optimization [BRAVO]; NCT01258829).
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http://dx.doi.org/10.1016/j.jcmg.2018.02.014DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6682561PMC
August 2019