Imperial College London

Dr Fu Siong Ng

Faculty of MedicineNational Heart & Lung Institute

Clinical Senior Lecturer in Cardiac Electrophysiology
 
 
 
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Contact

 

+44 (0)20 7594 3614f.ng Website

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

105 results found

Kim M-Y, Sandler B, Sikkel MB, Cantwell CD, Leong KM, Luther V, Malcolme-Lawes L, Koa-Wing M, Ng FS, Qureshi N, Sohaib A, Whinnett ZI, Fudge M, Lim E, Todd M, Wright I, Peters NS, Lim PB, Linton NWF, Kanagaratnam Pet al., 2020, The ectopy-triggering ganglionated plexuses in atrial fibrillation, Autonomic Neuroscience, Vol: 228, ISSN: 1566-0702

BackgroundEpicardial ganglionated plexus (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 “ET-GP” are upstream triggers of atrial ectopy/AF and have different anatomical distribution to AVD-GP.ObjectivesWe mapped and characterised ET-GP to understand their neural mechanism in AF and anatomical distribution in the left atrium (LA).Methods26 patients with paroxysmal AF were recruited. All were paced in the LA with an ablation catheter. HFS (80 ms) was synchronised to each paced stimulus (after 20 ms delay) 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.Results2302 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.ConclusionET-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.

Journal article

Keene D, Shun-Shin MJ, Arnold AD, March K, Qureshi N, Ng FS, Tanner M, Linton N, Lim PB, Lefroy D, Kanagaratnam P, Peters NS, Francis DP, Whinnett ZIet al., 2020, Within-patient comparison of His-bundle pacing, right ventricular pacing, and right ventricular pacing avoidance algorithms in patients with PR prolongation: Acute hemodynamic study, JOURNAL OF CARDIOVASCULAR ELECTROPHYSIOLOGY, ISSN: 1045-3873

Journal article

Brook J, Kim M-Y, Koutsoftidis S, Pitcher D, Agha-Jaffar D, Sufi A, Jenkins C, Tzortzis K, Ma S, Jabbour R, Houston C, Handa B, Li X, Chow J-J, Jothidasan A, Bristow P, Perkins J, Harding S, Bharath A, Ng FS, Peters N, Cantwell C, Chowdhury Ret al., 2020, Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling, Pflügers Archiv European Journal of Physiology, Vol: 472, Pages: 1435-1446, ISSN: 0031-6768

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap-junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting Porcine (n=9) and human (n=4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. 1mM of carbenoxolone was administered at 5ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed.We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9±4.1ms to 67.2±2.7ms) indicating conduction slowing. The features with the largest percentage change between baseline to Carbenoxolone were Fractionation +185.3%, Endpoint amplitude -106.9%, S-Endpoint Gradient +54.9%, S Point, -39.4%, RS Ratio +38.6% and (-dV/dt)max -20.9%.The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically-induced proarrhythmic substrates.

Journal article

Patel K, Jones T, Sattler S, Mason J, Ng FSet al., 2020, Pro-arrhythmic electrophysiological and structural remodelling in rheumatoid arthritis, American Journal of Physiology: Heart and Circulatory Physiology, ISSN: 0363-6135

Chronic inflammatory disorders, including rheumatoid arthritis (RA), are associated with a two-fold increase in the incidence of sudden cardiac death (SCD) compared to the healthy population. Although this is partly explained by an increased prevalence of coronary artery disease, growing evidence suggests that ischaemia alone cannot completely account for the increased risk. The present review explores the mechanisms of cardiac electrophysiological remodelling in response to chronic inflammation in RA. In particular, it focuses on the roles of non-ischaemic structural remodelling, altered cardiac ionic currents and autonomic nervous system dysfunction in ventricular arrhythmogenesis and SCD. It also explores whether common genetic elements predispose to both RA and SCD. Finally, it evaluates the potential dual effects of disease-modifying therapy in both diminishing and promoting the risk of ventricular arrhythmias and SCD.

Journal article

Ferraro E, Pozhidaeva L, Pitcher DS, Mansfield C, Koh JHB, Williamson C, Aslanidi O, Gorelik J, Ng FSet al., 2020, Prolonged ursodeoxycholic acid administration reduces acute ischaemia-induced arrhythmias in adult rat hearts, Scientific Reports, Vol: 10, Pages: 1-13, ISSN: 2045-2322

Acute myocardial ischaemiaand reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA)has previously been shown to be antiarrhythmic in fetal hearts.This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium,43andcomparesthe effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery(10 minutes), followed by reperfusion (2 minutes), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p=0.028),with a eduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment(10±3 vs 58±15, p=0.036).No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias.The antiarrhythmic effect of UDCA maybe partially mediated by an increase in cardiac wavelength, due tothe attenuation of conduction velocity slowing (p=0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia(p=0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.

Journal article

Sattler S, Baxan N, Ng FS, Benson L, Boyle J, Harding S, Rosenthal Net al., 2020, Myocardial damage induced by a single high dose of isoproterenol in C57BL/6J mice triggers a persistent adaptive immune response against the heart, Journal of Cellular and Molecular Medicine, ISSN: 1582-1838

Heart failure is the common final pathway of several cardiovascular conditions and a major cause of morbidity and mortality worldwide. Aberrant activation of the adaptive immune system in response to myocardial necrosis has recently been implicated in the development of heart failure. The ß-adrenergic agonist isoproterenol-hydrochloride isused for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis.To assess if isoproterenol-induced cardiomyocyte necrosistriggersan adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of 160mg/kg isoproterenol. We confirmed tissue damage reminiscent of human type 2 myocardial infarction. This is followed by an adaptive immune response targeting the heart as demonstrated by the activation of T cells, the presence of anti-heart auto-antibodies in the serum, as late as 12 weeks after initial challenge and IgG deposition in the myocardium. All of these are hallmark signs of an established autoimmune response. Adoptive transfer of splenocytes from isoproterenol-treated mice induces left ventricular dilation and impairs cardiac function in healthy recipients. In summary, a single administration of a high dose of isoproterenol is a suitable high-throughput model for future studies of the pathological mechanisms of anti-heart autoimmunity and to test potential immunomodulatory therapeutic approaches.

Journal article

Kim M-Y, Sandler B, Sikkel MB, Cantwell CD, Leong KM, Luther V, Malcolme-Lawes L, Koa-Wing M, Ng FS, Qureshi N, Sohaib A, Whinnett ZI, Fudge M, Lim E, Todd M, Wright I, Peters NS, Lim PB, Linton NWF, Kanagaratnam Pet al., 2020, The anatomical distribution of the ectopy-triggering ganglionated plexus in patients with atrial fibrillation, Circulation: Arrhythmia and Electrophysiology, Vol: 13, Pages: 1045-1047, ISSN: 1941-3084

Journal article

Ng FS, Handa B, Li X, Peters Net al., 2020, Towards mechanism-directed electrophenotype-based treatments for atrial fibrillation, Frontiers in Physiology, Vol: 11, Pages: 1-7, ISSN: 1664-042X

Current treatment approaches for persistent atrial fibrillation (AF) have a ceiling of success of around 50%. This is despite 15 years of developing adjunctive ablation strategies in addition to pulmonary vein isolation to target the underlying arrhythmogenic substrate in AF. A major shortcoming of our current approach to AF treatment is its predominantly empirical nature. This has in part been due to a lack of consensus on the mechanisms that sustain human AF.6 In this article, we review evidence suggesting that the previous debates on AF being eitheran organised arrhythmia with a focal driver ora disorganised rhythm sustained by multiple wavelets, may prove to be a false dichotomy. Instead,a range of fibrillation electrophenotypes exists along a continuous spectrum, and the predominant mechanism in an individual case is determined by the nature and extent of remodelling of the underlying substrate. We propose moving beyond the current empirical approach to AF treatment, and highlight the need to prescribe AF treatments based on the underlying AFelectrophenotype, and review several possible novel mapping algorithms that may be useful in discerning the AF electrophenotype to guide tailored treatments, including Granger Causality mapping.

Journal article

Sekelj S, Sandler B, Johnston E, Pollock KG, Hill NR, Gordon J, Tsang C, Khan S, Ng FS, Farooqui Uet al., 2020, Detecting undiagnosed atrial fibrillation in UK primary care: Validation of a machine learning prediction algorithm in a retrospective cohort study, European Journal of Preventive Cardiology, Pages: 1-9, ISSN: 2047-4873

AimsTo evaluate the ability of a machine learning algorithm to identify patients at high risk of atrial fibrillation in primary care.MethodsA retrospective cohort study was undertaken using the DISCOVER registry to validate an algorithm developed using a Clinical Practice Research Datalink (CPRD) dataset. The validation dataset included primary care patients in London, England aged ≥30 years from 1 January 2006 to 31 December 2013, without a diagnosis of atrial fibrillation in the prior 5 years. Algorithm performance metrics were sensitivity, specificity, positive predictive value, negative predictive value (NPV) and number needed to screen (NNS). Subgroup analysis of patients aged ≥65 years was also performed.ResultsOf 2,542,732 patients in DISCOVER, the algorithm identified 604,135 patients suitable for risk assessment. Of these, 3.0% (17,880 patients) had a diagnosis of atrial fibrillation recorded before study end. The area under the curve of the receiver operating characteristic was 0.87, compared with 0.83 in algorithm development. The NNS was nine patients, matching the CPRD cohort. In patients aged ≥30 years, the algorithm correctly identified 99.1% of patients who did not have atrial fibrillation (NPV) and 75.0% of true atrial fibrillation cases (sensitivity). Among patients aged ≥65 years (n = 117,965), the NPV was 96.7% with 91.8% sensitivity.ConclusionsThis atrial fibrillation risk prediction algorithm, based on machine learning methods, identified patients at highest risk of atrial fibrillation. It performed comparably in a large, real-world population-based cohort and the developmental registry cohort. If implemented in primary care, the algorithm could be an effective tool for narrowing the population who would benefit from atrial fibrillation screening in the United Kingdom.

Journal article

Handa BS, Li X, Aras KK, Qureshi NA, Mann I, Chowdhury RA, Whinnett ZI, Linton NWF, Lim PB, Kanagaratnam P, Efimov IR, Peters NS, Ng FSet al., 2020, Response by Handa et al to Letter Regarding Article, "Granger Causality-Based Analysis for Classification of Fibrillation Mechanisms and Localization of Rotational Drivers", CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY, Vol: 13, ISSN: 1941-3149

Journal article

Arnold AD, Howard JP, Gopi AA, Chan CP, Ali N, Keene D, Shun-Shin MJ, Ahmad Y, Wright IJ, Ng FS, Linton NWF, Kanagaratnam P, Peters NS, Rueckert D, Francis DP, Whinnett ZIet al., 2020, Discriminating electrocardiographic responses to His-bundle pacing using machine learning., Cardiovasc Digit Health J, Vol: 1, Pages: 11-20

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; P <.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.

Journal article

Handa B, Li X, Baxan N, Roney C, Shchendrygina A, Mansfield C, Jabbour R, Pitcher D, Chowdhury RA, Peters N, Ng FSet al., 2020, Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern, Cardiovascular Research, ISSN: 0008-6363

AimsConflicting data exist supporting differing mechanisms for sustaining ventricular fibrillation (VF), ranging from disorganised multiple-wavelet activation to organised rotational activities (RAs). Abnormal gap junction (GJ) coupling and fibrosis are important in initiation and maintenance of VF. We investigated whether differing ventricular fibrosis patterns and the degree of GJ coupling affected the underlying VF mechanism.Methods and ResultsOptical mapping of 65 Langendorff-perfused rat hearts was performed to study VF mechanisms in control hearts with acute GJ modulation, and separately in three differing chronic ventricular fibrosis models; compact (CF), diffuse (DiF) and patchy (PF). VF dynamics were quantified with phase mapping and frequency dominance index (FDI) analysis, a power ratio of the highest amplitude dominant frequency in the cardiac frequency spectrum.Enhanced GJ coupling with rotigaptide (n = 10) progressively organised fibrillation in a concentration-dependent manner; increasing FDI (0nM: 0.53±0.04, 80nM: 0.78±0.03, p < 0.001), increasing RA sustained VF time (0nM:44±6%, 80nM: 94±2%, p < 0.001) and stabilised RAs (maximum rotations for a RA; 0nM:5.4±0.5, 80nM: 48.2±12.3, p < 0.001). GJ uncoupling with carbenoxolone progressively disorganised VF; the FDI decreased (0µM: 0.60±0.05, 50µM: 0.17±0.03, p < 0.001) and RA-sustained VF time decreased (0µM: 61±9%, 50µM: 3±2%, p < 0.001).In CF, VF activity was disorganised and the RA-sustained VF time was the lowest (CF: 27±7% versus PF: 75±5%, p < 0.001). Global fibrillatory organisation measured by FDI was highest in PF (PF: 0.67±0.05 versus CF: 0.33±0.03, p < 0.001). PF harboured the longest duration and most spatially stable RAs (patchy: 1411&plusm

Journal article

Handa B, Li X, Aras KK, Qureshi NA, Mann I, Chowdhury R, Whinnett ZI, Linton NWF, Lim PB, Kanagaratnam P, Efimov IR, Peters N, Ng FSet al., 2020, Granger causality-based analysis for classification of fibrillation mechanisms and localisation of rotational drivers, Circulation: Arrhythmia and Electrophysiology, Vol: 12, Pages: 258-273, ISSN: 1941-3084

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: P=0.006, R2=0.38, 12.5% resolution, P=0.004, R2=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, P=0.0002).

Journal article

Li X, Handa BS, Peters NS, Ng FSet al., 2020, Classification of fibrillation subtypes with single-channel surface electrocardiogram, UK Workshop on Computational Intelligence (UKCI), Publisher: Springer International Publishing, Pages: 472-479, ISSN: 2194-5357

Atrial fibrillation (AF) and ventricular fibrillation (VF) are complex heart rhythm disorders with increasing prevalence. Mechanisms sustaining these arrhythmias are different, and subsequently, the required treatments options differ. Although many algorithms have been developed for differentiating fibrillation from normal sinus rhythm, very few methods exist to differentiate between different forms of AF and VF from surface electrocardiogram (ECG). To address the issue, we propose a novel ECG classification method to differentiate fibrillation that is completely chaotic from forms where it is organized with key driving sites. Differentiating fibrillation organisation from ECGs may aid patient selection, and identify those who may benefit from targeted ablation treatment. Evaluation using real-world data sets based on rat VF model shows that the proposed method could recognise the correct Fibrillation subtype from the single-channel electrocardiogram with an accuracy of 88.89 % .

Conference paper

Li X, Roney C, Handa B, Chowdhury R, Niederer S, Peters N, Ng FSet al., 2019, Standardised framework for quantitative analysisof fibrillation dynamics, Scientific Reports, Vol: 9, ISSN: 2045-2322

The analysis of complex mechanisms underlying ventricular fibrillation (VF) and atrial fibrillation (AF) requires sophisticatedtools for studying spatio-temporal action potential (AP) propagation dynamics. However, fibrillation analysis tools are oftencustom-made or proprietary, and vary between research groups. With no optimal standardised framework for analysis, resultsfrom different studies have led to disparate findings. Given the technical gap, here we present a comprehensive framework andset of principles for quantifying properties of wavefront dynamics in phase-processed data recorded during myocardial fibrillationwith potentiometric dyes. Phase transformation of the fibrillatory data is particularly useful for identifying self-perpetuating spiralwaves or rotational drivers (RDs) rotating around a phase singularity (PS). RDs have been implicated in sustaining fibrillation,and thus accurate localisation and quantification of RDs is crucial for understanding specific fibrillatory mechanisms. In thiswork, we assess how variation of analysis parameters and thresholds in the tracking of PSs and quantification of RDs couldresult in different interpretations of the underlying fibrillation mechanism. These techniques have been described and appliedto experimental AF and VF data, and AF simulations, and examples are provided from each of these data sets to demonstratethe range of fibrillatory behaviours and adaptability of these tools. The presented methodologies are available as an opensource software and offer an off-the-shelf research toolkit for quantifying and analysing fibrillatory mechanisms.

Journal article

Qureshi N, Kim S, Cantwell C, Afonso V, Bai WJ, Ali R, Shun-Shin M, Louisa M-L, Luther V, Leong K, Lim E, Wright I, Nagy S, Hayat S, Ng FS, Koa-Wing M, Linton N, Lefroy D, Whinnett Z, Davies DW, Kanagaratnam P, Peters N, Lim PBet al., 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, Vol: 16, Pages: 1357-1367, ISSN: 1547-5271

BackgroundBipolar electrogram voltage during sinus rhythm (VSR) has been used as a surrogate for atrial fibrosis in guiding catheter ablation of persistent AF, but the fixed rate and wavefront characteristics present during sinus rhythm may not accurately reflect underlying functional vulnerabilities responsible for AF maintenance.ObjectivesWe hypothesized that given adequate temporal sampling, the spatial distribution of mean AF voltage (VmAF) should better correlate with delayed-enhancement MRI (MRI-DE) detected atrial fibrosis than VSR.MethodsAF was mapped (8s) during index ablation for persistent AF (20 patients) using a 20-pole catheter (660±28 points/map). Following cardioversion, VSR was mapped (557±326 points/map). Electroanatomic and MRI-DE maps were co-registered in 14 patients.Results(i) The time course of VmAF was assessed from 1-40 AF-cycles (∼8s) at 1113 locations. VmAF stabilized with sampling >4s (mean voltage error=0.05mV). (ii) Paired point analysis of VmAF from segments acquired 30s apart (3,667-sites, 15-patients), showed strong correlation (r=0.95, p<0.001). (iii) Delayed-enhancement (DE) was assessed across the posterior left atrial (LA) wall, occupying 33±13%. VmAF distributions (median[IQR]) were 0.21[0.14-0.35]mV in DE vs. 0.52[0.34-0.77]mV in Non-DE regions. VSR distributions were 1.34[0.65-2.48]mV in DE vs. 2.37[1.27-3.97]mV in Non-DE. A VmAF threshold of 0.35mV yielded sensitivity/specificity 75%/79% in detecting MRI-DE, compared with 63%/67% for VSR (1.8mV threshold).ConclusionThe 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.

Journal article

Shun-Shin MJ, Leong KMW, Ng FS, Linton NWF, Whinnett ZI, Koa-Wing M, Qureshi N, Lefroy DC, Harding SE, Lim PB, Peters NS, Francis DP, Varnava AM, Kanagaratnam Pet al., 2019, Ventricular conduction stability test: a method to identify and quantify changes in whole heart activation patterns during physiological stress, EP-Europace, Vol: 21, Pages: 1422-1431, ISSN: 1099-5129

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.

Journal article

Keene D, Shun-Shin M, Arnold A, Howard J, Lefroy D, Davies W, Lim PB, Ng FS, Koa-Wing M, Qureshi N, Linton N, Shah J, Peters N, Kanagaratnam P, Francis D, Whinnett Zet al., 2019, Quantification of Electromechanical Coupling to Prevent Inappropriate Implantable Cardioverter-Defibrillator Shocks, JACC: Clinical Electrophysiology, Vol: 5, Pages: 705-715, ISSN: 2405-500X

Objective To test specialised processing of laser Doppler signals for discriminating ventricular fibrillation(VF) from common causes of inappropriate therapies.BackgroundInappropriate ICD therapies remain a clinically important problem associated with morbidity and mortality.Tissue perfusion biomarkers, to assist automated diagnosis of VF, suffer the vulnerability of sometimes mistaking artefact and random noise for perfusion, which could lead to shocks being inappropriately withheld. MethodsWe developed a novel processing algorithm that combines electrogram data and laser Doppler perfusion monitoring, as a method for assessing circulatory status. We recruited 50 patients undergoing VF induction during ICD implantation. We recorded non-invasive laser Doppler and continuous electrograms, during both sinus-rhythm and VF. For each patient we simulated two additional scenarios that may lead to inappropriate shocks: ventricular-lead fracture and T-wave oversensing. We analysed the laser Doppler using three methods for reducing noise: (i)Running Mean, (ii)Oscillatory Height, (iii)a novel quantification of Electro-Mechanical coupling which gates laser Doppler against electrograms. We additionally tested the algorithm during exercise induced sinus tachycardia.ResultsOnly the Electro-mechanical coupling algorithm found a clear perfusion cut-off between sinus rhythm and VF (sensitivity and specificity 100%). Sensitivity and specificity remained 100% during simulated lead fracture and electrogram oversensing. (AUC: Running Mean 0.91, Oscillatory Height 0.86, Electro-Mechanical Coupling 1.00). Sinus tachycardia did not cause false positives.ConclusionsQuantifying the coupling between electrical and perfusion signals increases reliability of discrimination between VF and artefacts that ICDs may interpret as VF. Incorporating such methods into future ICDs may safely permit reductions of inappropriate shocks.

Journal article

Handa B, Li X, Mansfield C, Jabbour RJ, Pitcher D, Chowdhury RA, Peters N, Ng FSet al., 2019, MYOCARDIAL FIBROSIS AND THE DEGREE OF GAP JUNCTION COUPLING DIRECTLY MODIFIES THE UNDERLYING MECHANISM OF FIBRILLATION, Annual Conference of the British-Cardiovascular-Society (BCS) - Digital Health Revolution, Publisher: BMJ PUBLISHING GROUP, Pages: A179-A180, ISSN: 1355-6037

Conference paper

Handa B, Lawal S, Wright IJ, Li X, Cabello Garcia J, Mansfield C, Chowdhury R, Peters N, Ng FSet al., 2019, Interventricular differences in action potential duration restitution contribute to dissimilar ventricular rhythms in ex vivo perfused hearts, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X

Background: Dissimilar ventricular rhythms refer to the occurrence of different ventricular tachyarrhythmias in the right and left ventricles or different rates of the same tachyarrhythmia in the two ventricles.Objective: We investigated the inducibility of dissimilar ventricular rhythms, their underlying mechanisms, and the impact of anti-arrhythmic drugs (lidocaine and amiodarone) on their occurrence.Methods: Ventricular tachyarrhythmias were induced with burst pacing in 28 Langendorff-perfused Sprague Dawley rat hearts (14 control, 8 lidocaine, 6 amiodarone) and bipolar electrograms recorded from the right and left ventricles. Fourteen (6 control, 4 lidocaine, 4 amiodarone) further hearts underwent optical mapping of transmembrane voltage to study interventricular electrophysiological differences and mechanisms of dissimilar rhythms.Results: In control hearts, dissimilar ventricular rhythms developed in 8/14 hearts (57%). In lidocaine treated hearts, there was a lower cycle length threshold for developing dissimilar rhythms, with 8/8 (100%) hearts developing dissimilar rhythms in comparison to 0/6 in the amiodarone group. Dissimilar ventricular tachycardia (VT) rates occurred at longer cycle lengths with lidocaine vs. control (57.1 ± 7.9 vs. 36.6 ± 8.4 ms, p < 0.001). The ratio of LV:RV VT rate was greater in the lidocaine group than control (1.91 ± 0.30 vs. 1.76 ± 0.36, p < 0.001). The gradient of the action potential duration (APD) restitution curve was shallower in the RV compared with LV (Control - LV: 0.12 ± 0.03 vs RV: 0.002 ± 0.03, p = 0.015), leading to LV-to-RV conduction block during VT.Conclusion: Interventricular differences in APD restitution properties likely contribute to the occurrence of dissimilar rhythms. Sodium channel blockade with lidocaine increases the likelihood of dissimilar ventricular rhythms.

Journal article

Odening KE, Deiß S, Dilling-Boer D, Didenko M, Eriksson U, Nedios S, Ng FS, Roca Luque I, Sanchez Borque P, Vernooy K, Wijnmaalen AP, Yorgun Het al., 2019, Mechanisms of sex differences in atrial fibrillation: role of hormones and differences in electrophysiology, structure, function, and remodelling, EP-Europace, Vol: 21, Pages: 366-376, ISSN: 1099-5129

Atrial fibrillation (AF) is the clinically most prevalent rhythm disorder with large impact on quality of life and increased risk for hospitalizations and mortality in both men and women. In recent years, knowledge regarding epidemiology, risk factors, and patho-physiological mechanisms of AF has greatly increased. Sex differences have been identified in the prevalence, clinical presentation, associated comorbidities, and therapy outcomes of AF. Although it is known that age-related prevalence of AF is lower in women than in men, women have worse and often atypical symptoms and worse quality of life as well as a higher risk for adverse events such as stroke and death associated with AF. In this review, we evaluate what is known about sex differences in AF mechanisms-covering structural, electrophysiological, and hormonal factors-and underscore areas of knowledge gaps for future studies. Increasing our understanding of mechanisms accounting for these sex differences in AF is important both for prognostic purposes and the optimization of (targeted, mechanism-based, and sex-specific) therapeutic approaches.

Journal article

Leong KMW, Ng FS, Jones S, Chow J-J, Qureshi N, Koa-Wing M, Linton NWF, Whinnett ZI, Lefroy DC, Davies DW, Lim PB, Peters NS, Kanagaratnam P, Varnava AMet al., 2019, Prevalence of spontaneous type I ECG pattern, syncope, and other risk markers in sudden cardiac arrest survivors with Brugada syndrome, PACE - Pacing and Clinical Electrophysiology, Vol: 42, Pages: 257-264, ISSN: 0147-8389

IntroductionA 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.MethodsAll 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.ResultsIn 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.ConclusionThe 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.

Journal article

Cantwell C, Mohamied Y, Tzortzis K, Garasto S, Houston C, Chowdhury R, Ng F, Bharath A, Peters Net al., 2019, Rethinking multiscale cardiac electrophysiology with machine learning and predictive modelling, Computers in Biology and Medicine, Vol: 104, Pages: 339-351, ISSN: 0010-4825

We review some of the latest approaches to analysing cardiac electrophysiology data using machine learning and predictive modelling. Cardiac arrhythmias, particularly atrial fibrillation, are a major global healthcare challenge. Treatment is often through catheter ablation, which involves the targeted localised destruction of regions of the myocardium responsible for initiating or perpetuating the arrhythmia. Ablation targets are either anatomically defined, or identified based on their functional properties as determined through the analysis of contact intracardiac electrograms acquired with increasing spatial density by modern electroanatomic mapping systems. While numerous quantitative approaches have been investigated over the past decades for identifying these critical curative sites, few have provided a reliable and reproducible advance in success rates. Machine learning techniques, including recent deep-learning approaches, offer a potential route to gaining new insight from this wealth of highly complex spatio-temporal information that existing methods struggle to analyse. Coupled with predictive modelling, these techniques offer exciting opportunities to advance the field and produce more accurate diagnoses and robust personalised treatment. We outline some of these methods and illustrate their use in making predictions from the contact electrogram and augmenting predictive modelling tools, both by more rapidly predicting future states of the system and by inferring the parameters of these models from experimental observations.

Journal article

Handa BS, Roney CH, Houston C, Qureshi N, Li X, Pitcher DS, Chowdhury RA, Lim PB, Dupont E, Niederer S, Cantwell C, Peters NS, Ng FSet al., 2018, Analytical approaches for myocardial fibrillation signals, Computers in Biology and Medicine, Vol: 102, Pages: 315-326, ISSN: 0010-4825

Atrial and ventricular fibrillation are complex arrhythmias, and their underlying mechanisms remain widely debated and incompletely understood. This is partly because the electrical signals recorded during myocardial fibrillation are themselves complex and difficult to interpret with simple analytical tools. There are currently a number of analytical approaches to handle fibrillation data. Some of these techniques focus on mapping putative drivers of myocardial fibrillation, such as dominant frequency, organizational index, Shannon entropy and phase mapping. Other techniques focus on mapping the underlying myocardial substrate sustaining fibrillation, such as voltage mapping and complex fractionated electrogram mapping. In this review, we discuss these techniques, their application and their limitations, with reference to our experimental and clinical data. We also describe novel tools including a new algorithm to map microreentrant circuits sustaining fibrillation.

Journal article

Roney C, Ng FS, Debney M, Eichhorn C, Nachiappan A, Chowdhury R, Qureshi N, Cantwell C, Tweedy J, Niederer S, Peters N, Vigmond Eet al., 2018, Determinants of new wavefront locations in cholinergic atrial fibrillation, EP-Europace, Vol: 20, Pages: iii3-iii15, ISSN: 1099-5129

AimsAtrial fibrillation (AF) wavefront dynamics are complex and difficult to interpret, contributing to uncertainty about the mechanisms that maintain AF. We aimed to investigate the interplay between rotors, wavelets, and focal sources during fibrillation.Methods and resultsArrhythmia wavefront dynamics were analysed for four optically mapped canine cholinergic AF preparations. A bilayer computer model was tuned to experimental preparations, and varied to have (i) fibrosis in both layers or the epicardium only, (ii) different spatial acetylcholine distributions, (iii) different intrinsic action potential duration between layers, and (iv) varied interlayer connectivity. Phase singularities (PSs) were identified and tracked over time to identify rotational drivers. New focal wavefronts were identified using phase contours. Phase singularity density and new wavefront locations were calculated during AF. There was a single dominant mechanism for sustaining AF in each of the preparations, either a rotational driver or repetitive new focal wavefronts. High-density PS sites existed preferentially around the pulmonary vein junctions. Three of the four preparations exhibited stable preferential sites of new wavefronts. Computational simulations predict that only a small number of connections are functionally important in sustaining AF, with new wavefront locations determined by the interplay between fibrosis distribution, acetylcholine concentration, and heterogeneity in repolarization within layers.ConclusionWe were able to identify preferential sites of new wavefront initiation and rotational activity, in order to determine the mechanisms sustaining AF. Electrical measurements should be interpreted differently according to whether they are endocardial or epicardial recordings.

Journal article

Sattler S, Ng FS, Panahi M, 2018, Immunopharmacology of post-myocardial infarction and heart failure medications, Journal of Clinical Medicine, Vol: 7, ISSN: 2077-0383

The immune system responds to acute tissue damage after myocardial infarction (MI) and orchestrates healing and recovery of the heart. However, excessive inflammation may lead to additional tissue damage and fibrosis and exacerbate subsequent functional impairment, leading to heart failure. The appreciation of the immune system as a crucial factor after MI has led to a surge of clinical trials investigating the potential benefits of immunomodulatory agents previously used in hyper-inflammatory conditions, such as autoimmune disease. While the major goal of routine post-MI pharmacotherapy is to support heart function by ensuring appropriate blood pressure and cardiac output to meet the demands of the body, several drug classes also affect a range of immunological pathways and modulate the post-MI immune response, which is crucial to take into account when designing future immunomodulatory trials. This review outlines how routine post-MI pharmacotherapy affects the immune response and may thus influence post-MI outcomes and development towards heart failure. Current key drug classes are discussed, including platelet inhibitors, statins, β-blockers, and renin–angiotensin–aldosterone inhibitors.

Journal article

Luther V, Wright I, Lefroy D, Ng Fet al., 2018, A narrow complex tachycardia with variable R-R intervals: what is the mechanism?, Journal of Cardiovascular Electrophysiology, Vol: 29, Pages: 1174-1176, ISSN: 1045-3873

A 46-year-old man was referred for an invasive electrophysiological study with a view to ablation, for a history of classic sudden onset-offset palpitations. The patient’s son had recently survived an out of hospital cardiac arrest, and was found to have an accessory pathway (details unknown) at another institute, which was ablated. Our patient’s 12 lead electrocardiogram (ECG) showed sinus rhythm with no evidence of pre-excitation. Echocardiography revealed a structurally normal heart. An electrophysiological study was performed with a quadripolar catheter positioned at the high right atrium (HRA), a steerable decapolar catheter in the coronary sinus and quadripolar catheters along the His bundle and at the right ventricular apex. Baseline atrio-His (AH) and His-ventricular (HV) intervals measured 60ms and 40ms respectively. Programmed atrial extra-stimulus testing revealed decremental AH intervals, before tachycardia was reproducibly induced. Figure 1 shows the tachycardia on a 12-lead ECG. Figure 2 shows the induction of tachycardia with atrial pacing. Based on the findings within the figures, what is the mechanism of the tachycardia?

Journal article

Jabbour R, Kapnisi K, Mawad D, Handa B, Couch L, Mansfield C, Perbillini F, Terracciano C, Stevens M, Lyon A, Smith G, Peters N, Ng FS, Harding Set al., 2018, Conductive polymers affect myocardial conduction velocity but are not pro-arrhythmic, European-Society-of-Cardiology Congress, Publisher: OXFORD UNIV PRESS, Pages: 1205-1205, ISSN: 0195-668X

Conference paper

Houston CPJ, Tzortzis KN, Roney C, Saglietto A, Pitcher DS, Cantwell C, Chowdhury RA, Ng FS, Peters NS, Dupont Eet al., 2018, Characterisation of re-entrant circuit (or rotational activity) in vitro using the HL1-6 myocyte cell line, Journal of Molecular and Cellular Cardiology, Vol: 119, Pages: 155-164, ISSN: 0022-2828

Fibrillation is the most common arrhythmia observed in clinical practice. Understanding of the mechanisms underlying its initiation and maintenance remains incomplete. Functional re-entries are potential drivers of the arrhythmia. Two main concepts are still debated, the “leading circle” and the “spiral wave or rotor” theories. The homogeneous subclone of the HL1 atrial-derived cardiomyocyte cell line, HL1-6, spontaneously exhibits re-entry on a microscopic scale due to its slow conduction velocity and the presence of triggers, making it possible to examine re-entry at the cellular level.We therefore investigated the re-entry cores in cell monolayers through the use of fluorescence optical mapping at high spatiotemporal resolution in order to obtain insights into the mechanisms of re-entry.Re-entries in HL1-6 myocytes required at least two triggers and a minimum colony area to initiate (3.5 to 6.4 mm2). After electrical activity was completely stopped and re-started by varying the extracellular K+ concentration, re-entries never returned to the same location while 35% of triggers re-appeared at the same position. A conduction delay algorithm also allows visualisation of the core of the re-entries. This work has revealed that the core of re-entries is conduction blocks constituted by lines and/or groups of cells rather than the round area assumed by the other concepts of functional re-entry. This highlights the importance of experimentation at the microscopic level in the study of re-entry mechanisms.

Journal article

Chowdhury RA, Tzortzis KN, Dupont E, Selvadurai S, Perbellini F, Cantwell C, Ng FS, Simon A, Terracciano C, Peters NSet al., 2018, Concurrent micro- to macro-cardiac electrophysiology in myocyte cultures and human heart slices, Scientific Reports, Vol: 8, ISSN: 2045-2322

The contact cardiac electrogram is derived from the extracellular manifestation of cellular action potentials and cell-to-cell communication. It is used to guide catheter based clinical procedures. Theoretically, the contact electrogram and the cellular action potential are directly related, and should change in conjunction with each other during arrhythmogenesis, however there is currently no methodology by which to concurrently record both electrograms and action potentials in the same preparation for direct validation of their relationships and their direct mechanistic links. We report a novel dual modality apparatus for concurrent electrogram and cellular action potential recording at a single cell level within multicellular preparations. We further demonstrate the capabilities of this system to validate the direct link between these two modalities of voltage recordings.

Journal article

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