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 2735f.ng Website

 
 
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Location

 

430ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
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145 results found

Ardissino M, Rajasundaram S, Reddy R, Ng F, Gill Det al., 2022, Safety of beta-blocker and calcium channel blocker antihypertensive drugs in pregnancy: a Mendelian randomization study, BMC Medicine, Vol: 20, ISSN: 1741-7015

Background: Beta-blocker (BB) and calcium channel blocker (CCB)antihypertensive drugs are commonly used in pregnancy. However, data on theirrelative impact on maternal and fetal outcomes are limited. We leveraged geneticvariants mimicking BB and CCB antihypertensive drugs to investigate their effects onrisk of pre-eclampsia, gestational diabetes and birthweight using the Mendelianrandomization paradigm.Methods: Genetic association estimates for systolic blood pressure (SBP) wereextracted from summary data of a genome-wide association study (GWAS) on757,601 participants. Uncorrelated single-nucleotide polymorphisms (SNPs)associated with SBP (p<5x10-8) in BB and CCB drug target gene regions wereselected as proxies for drug target perturbation. Genetic association estimates forthe outcomes were extracted from GWASs on 4,743 cases and 136,325 controls(women without a hypertensive disorder in pregnancy) for pre-eclampsia oreclampsia, 7,676 cases and 130,424 controls (women without any pregnancy-relatedmorbidity) for gestational diabetes, and 155,202 women (who have given birth atleast once) for birthweight of the first child. All studies were in European ancestrypopulations. Mendelian randomization estimates were generated using the twosample inverse-variance weighted model.Results: Although not reaching the conventional threshold for statistical significance,genetically-proxied BB was associated with reduced risk of pre-eclampsia (OR per10mmHg SBP reduction 0.27, 95%CI 0.06-1.19, p=0.08) and increased risk ofgestational diabetes (OR per 10mmHg SBP reduction 2.01, 95%CI 0.91-4.42,p=0.08), and significantly associated with lower birthweight of first child (beta per 10mmHg SBP reduction -0.27, 95%CI -0.39 to -0.15, p=1.90x10-5). Geneticallyproxied CCB was associated with reduced risk of pre-eclampsia and eclampsia (OR0.62, 95%CI 0.43-0.89, p=9.33x10-3), and was not associated with gestationaldiabetes (OR 1.05, 95% CI 0.76-1.45, p=0.76) or changes in birthweight of first

Journal article

Kim MY, Nesbitt J, Koutsoftidis S, Brook J, Pitcher D, Cantwell C, Handa B, Jenkins C, Houston C, Rothery S, Jothidasan A, Perkins J, Bristow P, Linton N, Drakakis E, Peters N, Chowdhury R, Kanagaratnam P, Ng FSet al., 2022, Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high frequency stimulation, EP Europace, ISSN: 1099-5129

Introduction: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). Objective: To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS. Methods: 63 atrial sites were tested with HFS in 4 Langendorff-perfused porcine hearts. A 3.5mm tip quadripolar ablation catheter was used to stimulate and deliver HFS to the left and right atrial epicardium, within the local atrial refractory period. Tissue samples from sites triggering atrial ectopy/AF (ET) sites and non-ET sites were stained with choline acetyl transferase (ChAT) and tyrosine hydroxylase (TH), for quantification of parasympathetic and sympathetic nerves, respectively. The average cross-sectional area (CSA) of nerves was also calculated.Results: Histomorphometry of 6 ET sites (9.5%) identified by HFS evoking at least a single atrial ectopic was compared with non-ET sites. All ET sites contained ChAT-immunoreactive (ChAT-IR) and/or TH-immunoreactive nerves (TH-IR). Nerve density was greater in ET sites compared to non-ET sites (nerves/cm2: 162.3 ±110.9 vs 69.65 ±72.48; p=0.047). Overall, TH-IR nerves had larger CSA than ChAT-IR nerves (µm2: 11,196 ± 35,141 vs 2,070 ± 5,841; p<0.0001), but in ET sites, TH-IR nerves were smaller than in non-ET sites (µm2: 6,021±14,586 vs 25,254 ± 61,499; p<0.001).Conclusions: ET sites identified by HFS contained higher density of smaller nerves than non-ET sites. Majority of these nerves were within the atrial myocardium. This has important clinical implications on devising an effective therapeutic strategy for targeting autonomic triggers of AF.

Journal article

Sau A, Ibrahim S, Ahmed A, Handa B, Kramer DB, Waks JW, Arnold AD, Howard JP, Qureshi N, Koa-Wing M, Keene D, Malcolme-Lawes L, Lefroy DC, Linton NWF, Lim PB, Varnava A, Whinnett ZI, Kanagaratnam P, Mandic D, Peters NS, Ng FSet al., 2022, Artificial intelligence-enabled electrocardiogram to distinguish cavotricuspid isthmus dependence from other atrial tachycardia mechanisms, European Heart Journal – Digital Health, ISSN: 2634-3916

Journal article

Patel K, li X, xu X, Lin S, maddalena A, Punjabi P, Purkayastha S, Peters NS, Ware JS, Ng FSet al., 2022, Increasing adiposity is associated with QTc interval prolongation and increased ventricular arrhythmic risk in the context of metabolic dysfunction: results from the UK Biobank, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-11, ISSN: 2297-055X

Background: Small-scale studies have linked obesity (Ob) and metabolic ill-health with proarrhythmic repolarisation abnormalities. Whether these are observed at a population-scale, modulated by individuals’ genetics and confer higher risks of ventricular arrhythmias (VA) are not known. Methods and Results: Firstly, using the UK Biobank, the association between adiposity and QTc interval was assessed in participants with resting 12-lead ECG (n=23,683), and a polygenic risk score was developed to investigate any modulatory effect of genetics. Participants were also categorised into four phenotypes according to presence (+) or absence (-) of Ob, and if they were metabolically unhealthy (MU+) or not (MU-). QTc was positively associated with body mass index, body fat, waist:hip ratio, and hip and waist girths. Individuals’ genetics had no significant modulatory effect on QTc-prolonging effects of increasing adiposity. QTc was comparably longer in those with metabolic perturbationwithout obesity (Ob-MU+) and obesity alone (Ob+MU-) compared to individuals with neither (Ob-MU-), and their co-existence (Ob+MU+) had an additive effect on QTc interval. Secondly, for 502,536 participants in the UK Biobank, odds ratios (OR) for ventricular arrhythmias (VA) were computed for the four clinical phenotypes above using their past medical records. Referenced to Ob-MU-, ORs for VA in Ob-MU+ males and females were 5.96 (95%CI: 4.70-7.55) and 5.10 (95%CI: 3.34-7.80), respectively. OR for Ob+MU+ were 6.99 (95%CI: 5.72-8.54) and 3.56 (95%CI: 2.66-4.77) in males and females, respectively. Conclusion: Adiposity and metabolic perturbation increase QTc to a similar degree, and their co-existence exerts an additive effect. These effects are not modulated by individuals’ genetics. Metabolic ill-health is associated with higher OR for VA than obesity.

Journal article

Falkenberg McGillivray M, Coleman JA, Dobson S, Hickey DJ, Terrill L, Ciacci A, Thomas B, Sau A, Ng FS, Zhao J, Peters N, Christensen Ket al., 2022, Identifying locations susceptible to micro-anatomical reentry using a spatial network representation of atrial fibre maps, PLoS One, Vol: 17, Pages: 1-24, ISSN: 1932-6203

Micro-anatomical reentry has been identified as a potential driver of atrial fibrillation (AF). In this paper, we introduce a novel computational method which aims to identify which atrial regions are most susceptible to micro-reentry. The approach, which considers the structural basis for micro-reentry only, is based on the premise that the accumulation of electrically insulating interstitial fibrosis can be modelled by simulating percolation-like phenomena on spatial networks. Our results suggest that at high coupling, where micro-reentry is rare, the micro-reentrant substrate is highly clusteredin areas where the atrial walls are thin and have convex wall morphology, likely facilitating localised treatment via ablation. However, as transverse connections between fibres are removed, mimicking the accumulation of interstitial fibrosis, the substrate becomes less spatially clustered, and the bias to forming in thin, convex regions of the atria is reduced, possibly restricting the efficacy of localised ablation. Comparing our algorithm on image-based models with and without atrial fibre structure, we find thatstrong longitudinal fibre coupling can suppress the micro-reentrant substrate, whereas regions with disordered fibre orientations have an enhanced risk of micro-reentry. With further development, these methods may be useful for modelling the temporal development of the fibrotic substrate on an individualised basis.

Journal article

Sivanandarajah P, Wu H, Bajaj N, Khan S, Ng FSet al., 2022, Is machine learning the future for atrial fibrillation screening?, Cardiovascular Digital Health Journal, Vol: 3, Pages: 136-145, ISSN: 2666-6936

Atrial fibrillation (AF) is the most common arrhythmia and causes significant morbidity and mortality. Early identification of AF may lead to early treatment of AF and may thus prevent AF-related strokes and complications. However, there is no current formal, cost-effective strategy for population screening for AF. In this review, we give a brief overview of targeted screening for AF, AF risk score models used for screening and describe the different screening tools. We then go on to extensively discuss the potential applications of machine learning in AF screening.

Journal article

Nagy SZ, Kasi P, Afonso VX, Bird N, Pederson B, Mann IE, Kim S, Linton NWF, Lefroy DC, Whinnett Z, Ng FS, Koa-Wing M, Kanagaratnam P, Peters NS, Qureshi NA, Lim PBet al., 2022, Cycle length evaluation in persistent atrial fibrillation using kernel density estimation to identify transient and stable rapid atrial activity, Cardiovascular Engineering and Technology, Vol: 13, Pages: 219-233, ISSN: 1869-408X

PurposeLeft atrial (LA) rapid AF activity has been shown to co-localise with areas of successful atrial fibrillation termination by catheter ablation. We describe a technique that identifies rapid and regular activity.MethodsEight-second AF electrograms were recorded from LA regions during ablation for psAF. Local activation was annotated manually on bipolar signals and where these were of poor quality, we inspected unipolar signals. Dominant cycle length (DCL) was calculated from annotation pairs representing a single activation interval, using a probability density function (PDF) with kernel density estimation. Cumulative annotation duration compared to total segment length defined electrogram quality. DCL results were compared to dominant frequency (DF) and averaging.ResultsIn total 507 8 s AF segments were analysed from 7 patients. Spearman’s correlation coefficient was 0.758 between independent annotators (P < 0.001), 0.837–0.94 between 8 s and ≥ 4 s segments (P < 0.001), 0.541 between DCL and DF (P < 0.001), and 0.79 between DCL and averaging (P < 0.001). Poorer segment organization gave greater errors between DCL and DF.ConclusionDCL identifies rapid atrial activity that may represent psAF drivers. This study uses DCL as a tool to evaluate the dynamic, patient specific properties of psAF by identifying rapid and regular activity. If automated, this technique could rapidly identify areas for ablation in psAF.

Journal article

Kim M-Y, Coyle C, Tomlinson DR, Sikkel MB, Sohaib A, Luther V, Leong KM, Malcolme-Lawes L, Low B, Sandler B, Lim E, Todd M, Fudge M, Wright I, Koa-Wing M, Ng FS, Qureshi NA, Whinnett ZI, Peters NS, Newcomb D, Wood C, Dhillon G, Hunter RJ, Lim PB, Linton NW, Kanagaratnam Pet al., 2022, Ectopy-triggering ganglionated plexus ablation to prevent atrial fibrillation: GANGLIA-AF study., Heart Rhythm, Vol: 19, Pages: 516-524, ISSN: 1547-5271

BACKGROUND: The ganglionated plexuses (GP) of the intrinsic cardiac autonomic system may play a role in atrial fibrillation (AF). OBJECTIVES: We hypothesized that ablating the ectopy-triggering GPs (ET-GP) prevents AF. METHODS: GANGLIA-AF (NCT02487654) was a prospective, randomized, controlled, 3-centre trial. ET-GP were mapped using high frequency stimulation (HFS), delivered within the atrial refractory period and ablated until non-functional. If triggered AF became incessant, atrioventricular dissociating GPs (AVD-GP) were ablated. We compared GP ablation (GPA) without pulmonary vein isolation (PVI) against PVI, in patients with paroxysmal AF. Follow-up was for 12 months including 3-monthly 48hr Holter monitors. The primary endpoint was documented ≥30s atrial arrhythmia after a 3-month blanking period. RESULTS: 102 randomized patients were analysed on a per-protocol basis after GPA (n=52) or PVI (n=50). GPA patients had 89±26 HFS sites tested, identifying median 18.5 (IQR 16; 21%) GPs. RF ablation time in GPA was 22.9±9.8mins and 38±14.4mins in PVI (p<0.0001). The freedom from ≥30s atrial arrhythmia at 12-month follow-up with GPA was 50% (26/52) vs 64% (32/50) with PVI (log rank p=0.09). ET-GP ablation without AVD-GP ablation achieved 58% (22/38) freedom from the primary endpoint. There was a significantly higher reduction in AAD usage post-ablation after GPA vs PVI (55.5% vs 36%; p=0.05). Patients were referred for redo ablations in 31% (16/52) after GPA and 24% (12/50) after PVI (p=0.53). CONCLUSIONS: GPA did not prevent atrial arrhythmias more than PVI. However, less RF ablation was delivered to achieve a higher reduction in AAD usage with GPA than PVI.

Journal article

Sau A, Kaura A, Ahmed A, Patel KHK, Li X, Mulla A, Glampson B, Panoulas V, Davies J, Woods K, Gautama S, Shah AD, Elliott P, Hemingway H, Williams B, Asselbergs FW, Melikian N, Peters NS, Shah AM, Perera D, Kharbanda R, Patel RS, Channon KM, Mayet J, Ng FSet al., 2022, Prognostic significance of ventricular arrhythmias in 13444 patients with acute coronary syndrome: a retrospective cohort study based on routine clinical data (NIHR Health Informatics Collaborative VA-ACS Study), Journal of the American Heart Association, Vol: 11, Pages: 1-19, ISSN: 2047-9980

Background: A minority of acute coronary syndrome (ACS) cases are associated with ventricular arrhythmias (VA) and/or cardiac arrest (CA). We investigated the effect of VA/CA at time of ACS on long-term outcomes.Methods and Results: We analysed routine clinical data from 5 NHS Trusts in the United Kingdom, collected between 2010 and 2017, by the National Institute for Health Research Health Informatics Collaborative (NIHR HIC).13,444 patients with ACS, of which 376 (2.8%) had concurrent VA, survived to hospital discharge and were followed up for a median of 3.42 years. Patients with VA or CA at index presentation had significantly increased risks of subsequent VA during follow-up (VA group: adjusted HR 4.15, 95% CI 2.42-7.09, CA group: adjusted HR 2.60 95% CI 1.23-5.48). Patients who suffered a CA in the context of ACS and survived to discharge also had a 36% increase in long-term mortality (adjusted hazard ratio 1.36 (95% 1.04-1.78)), though the concurrent diagnosis of VA alone during ACS did not affect all-cause mortality (adjusted HR 1.03, 95% CI 0.80-1.33). Conclusions: Patients who develop VA or CA during ACS, who survive to discharge, have increased risks of subsequent VA, while those who have CA during ACS also have an increase in long-term mortality. These individuals may represent a subgroup at greater risk of subsequent arrhythmic events due to intrinsically lower thresholds for developing VA.

Journal article

Ardissino M, Slob E, Millar O, Reddy R, Lazzari L, Patel KHK, Ryan D, Johnson M, Gill D, Ng FSet al., 2022, Maternal hypertension increases risk of pre-eclampsia and low fetal birthweight: genetic evidence from a Mendelian randomization study, Hypertension, Vol: 79, Pages: 1-11, ISSN: 0194-911X

Background: Maternal cardiovascular risk factors have been associated with adverse maternal and fetal outcomes. Given the difficulty in establishing causal relationships using epidemiological data, we applied Mendelian randomization to explore the role of cardiovascular risk factors on risk of developing pre-eclampsia or eclampsia, and low fetal birthweight.Methods: Uncorrelated single nucleotide polymorphisms associated systolic blood pressure, body mass index, type 2 diabetes mellitus, low-density lipoprotein with cholesterol, smoking, urinary albumin-to-creatinine ratio and estimated glomerular filtration rate at genome-wide significance in studies of 298,957 to 1,201,909 European ancestry participants were selected as instrumental variables. A two-sample Mendelian randomization study was performed with primary outcome of pre-eclampsia or eclampsia (PET). Risk factors associated with PET were further investigated for their association with low birthweight. Results: Higher genetically-predicted systolic blood pressure was associated increased risk of PET [odds ratio (OR) per 1-SD systolic blood pressure increase 1.90 (95% confidence interval (CI)1.45-2.49;p=3.23x10-6 and reduced birthweight (OR=0.83; 95%CI=0.79-0.86;p=3.96x10-18), and this was not mediated by PET. Body mass index and type 2 diabetes were also associated with PET (respectively, OR per 1-SD body mass index increase=1.67 95%CI=1.44-1.94,;p=7.45x10-12; and OR per logOR increase type 2 diabetes=1.11 95%CI=1.04-1.19p;=1.19x10-3), but not with reduced birthweight. Conclusions: Our results provide evidence for causal effects of systolic blood pressure, body mass index and type 2 diabetes on PET, and identify that systolic blood pressure is associated with reduced birthweight independently of PET. The results provide insight into the pathophysiological basis of PET and identify hypertension as a potentially modifiable risk factor amenable to therapeutic intervention.

Journal article

Ardissino M, Reddy RK, Slob EAW, Patel KHK, Ryan DK, Gill D, Ng FSet al., 2022, Sleep disordered breathing, obesity and atrial fibrillation: a mendelian randomisation study, Geneses, Vol: 13, Pages: 1-11, ISSN: 1155-3219

It remains unclear whether the association between obstructive sleep apnoea (OSA), a form of sleep-disordered breathing (SDB), and atrial fibrillation (AF) is causal or mediated by shared co-morbidities such as obesity. Existing observational studies are conflicting and limited by confounding and reverse causality. We performed Mendelian randomisation (MR) to investigate the causal relationships between SDB, body mass index (BMI) and AF. Single-nucleotide polymorphisms associated with SDB (n = 29) and BMI (n = 453) were selected as instrumental variables to investigate the effects of SDB and BMI on AF, using genetic association data on 55,114 AF cases and 482,295 controls. Primary analysis was conducted using inverse-variance weighted MR. Higher genetically predicted SDB and BMI were associated with increased risk of AF (OR per log OR increase in snoring liability 2.09 (95% CI 1.10–3.98), p = 0.03; OR per 1-SD increase in BMI 1.33 (95% CI 1.24–1.42), p < 0.001). The association between SDB and AF was not observed in sensitivity analyses, whilst associations between BMI and AF remained consistent. Similarly, in multivariable MR, SDB was not associated with AF after adjusting for BMI (OR 0.68 (95% CI 0.42–1.10), p = 0.12). Higher BMI remained associated with increased risk of AF after adjusting for OSA (OR 1.40 (95% CI 1.30–1.51), p < 0.001). Elevated BMI appears causal for AF, independent of SDB. Our data suggest that the association between SDB, in general, and AF is attributable to mediation or confounding from obesity, though we cannot exclude that more severe SDB phenotypes (i.e., OSA) are causal for AF.

Journal article

Patel K, Hwang T, Se Liebers C, Ng FSet al., 2021, Epicardial adipose tissue as a mediator of cardiac arrhythmias, American Journal of Physiology: Heart and Circulatory Physiology, Vol: 322, ISSN: 0363-6135

Obesity is associated with higher risks of cardiac arrhythmias. Although this may be partly explained by concurrent cardiometabolic ill-health, growing evidence suggests that increasing adiposity independently confers risk for arrhythmias. Amongst fat depots, epicardial adipose tissue (EAT) exhibits a proinflammatory secretome, and given the lack of fascial separation, has been implicated as a transducer of inflammation to the underlying myocardium. The present review explores the mechanisms underpinning adverse electrophysiological remodelling as a consequence of EAT accumulation and the consequent inflammation. We first describe the physiological and pathophysiological function of EAT and its unique secretome, and subsequently discuss the evidence for ionic channel and connexin expression modulation as well as fibrotic remodelling induced by cytokines and free fatty acids that are secreted by EAT. Finally, we highlight how weight reduction and regression of EAT volume may cause reverse remodelling to ameliorate arrhythmic risk.

Journal article

Patel K, Li X, Sun L, Peters N, Ng FSet al., 2021, Neural networks applied to 12-lead electrocardiograms predict body mass index, visceral adiposity and concurrent cardiometabolic ill-health, Cardiovascular Digital Health Journal, Vol: 2, Pages: S1-S10, ISSN: 2666-6936

BackgroundObesity is associated with electrophysiological remodeling, which manifests as detectable changes on the surface electrocardiogram (ECG).ObjectiveTo develop neural networks (NN) to predict body mass index (BMI) from ECGs and test the hypothesis that discrepancies between NN-predicted BMI and measured BMI are indicative of underlying adiposity and/or concurrent cardiometabolic ill-health.MethodsNN models were developed using 36,856 12-lead resting ECGs from the UK Biobank. Two architectures were developed for continuous and categorical BMI estimation (normal weight [BMI <25 kg/m2] vs overweight/obese [BMI ≥25 kg/m2]). Models for male and female participants were trained and tested separately. For each sex, data were randomly divided into 4 folds, and models were evaluated in a leave-1-fold-out manner.ResultsECGs were available for 17,807 male and 19,049 female participants (mean ages: 61 ± 7 and 63 ± 8 years; mean BMI 26 ± 5 kg/m2 and 27 ± 4 kg/m2, respectively). NN models detected overweight/obese individuals with average accuracies of 75% and 73% for male and female subjects, respectively. The magnitudes of difference between NN-predicted BMI and actual BMI were significantly correlated with visceral adipose tissue volumes. Concurrent hypertension, diabetes, dyslipidemia, and/or coronary heart disease explained false-positive classifications (ie, calculated BMI <25 kg/m2 misclassified as ≥25 kg/m2 by NN model, P < .001).ConclusionNN models applied to 12-lead ECGs predict BMI with a reasonable degree of accuracy. Discrepancies between NN-predicted and calculated BMI may be indicative of underlying visceral adiposity and concomitant cardiometabolic perturbation, which could be used to identify individuals at risk of cardiometabolic disease.

Journal article

Ardissino M, Millar O, Reddy R, Lazzari L, Patel K, Ryan D, Gill D, Johnson M, Ng FSet al., 2021, Effect of Cardiovascular Risk Factors on Hypertensive Disorders of Pregnancy: A Mendelian Randomization Study, Publisher: LIPPINCOTT WILLIAMS & WILKINS, ISSN: 0009-7322

Conference paper

Chow J-J, Leong KMW, Yazdani M, Huzaien HW, Jones S, Shun-Shin MJ, Koa-Wing M, Lefroy DC, Lim PB, Linton NWF, Ng FS, Qureshi NA, Whinnett ZI, Peters NS, O'Callaghan P, Yousef Z, Kanagaratnam P, Varnava AMet al., 2021, A Multicenter External Validation of a Score Model to Predict Risk of Events in Patients With Brugada Syndrome, AMERICAN JOURNAL OF CARDIOLOGY, Vol: 160, Pages: 53-59, ISSN: 0002-9149

Journal article

Hartley A, Shalhoub J, Ng F, Krahn A, Laksman Z, Andrade J, Deyell M, Kanagaratnam P, Sikkel Met al., 2021, Size matters in atrial fibrillation: the underestimated importance of reduction of contiguous electrical mass underlying the effectiveness of catheter ablation, Europace, Vol: 23, Pages: 1698-1707, ISSN: 1099-5129

Evidence has accumulated over the last century of the importance of a critical electrical mass in sustaining atrial fibrillation (AF). AF ablation certainly reduces electrically contiguous atrial mass, but this is not widely accepted to be an important part of its mechanism of action. In this article, we review data showing that atrial size is correlated in many settings with AF propensity. Larger mammals are more likely to exhibit AF. This is seen both in the natural world and in animal models, where it is much easier to create a goat model than a mouse model of AF, for example. This also extends to humans—athletes, taller people, and obese individuals all have large atria and are more likely to exhibit AF. Within an individual, risk factors such as hypertension, valvular disease and ischaemia can enlarge the atrium and increase the risk of AF. With respect to AF ablation, we explore how variations in ablation strategy and the relative effectiveness of these strategies may suggest that a reduction in electrical atrial mass is an important mechanism of action. We counter this with examples in which there is no doubt that mass reduction is less important than competing theories such as ganglionated plexus ablation. We conclude that, when considering future strategies for the ablative therapy of AF, it is important not to discount the possibility that contiguous electrical mass reduction is the most important mechanism despite the disappointing consequence being that enhancing success rates in AF ablation may involve greater tissue destruction.

Journal article

Li X, Shi X, Handa BS, Sau A, Zhang B, Qureshi NA, Whinnett ZI, Linton N, Lim PB, Kanagaratnam P, Peters N, Ng FSet al., 2021, Classification of fibrillation organisation using electrocardiograms to guide mechanism-directed treatments, Frontiers in Physiology, Vol: 12, Pages: 1-14, ISSN: 1664-042X

Background: Atrial fibrillation (AF) and ventricular fibrillation (VF) are complex heart rhythm disorders and may be sustained by distinct electrophysiological mechanisms. Disorganised self-perpetuating multiple-wavelets and organised rotational drivers (RDs) localising to specific areas are both possible mechanisms by which fibrillation is sustained. Determining the underlying mechanisms of fibrillation may be helpful in tailoring treatment strategies. We investigated whether global fibrillation organisation, a surrogate for fibrillation mechanism, can be determined from electrocardiograms (ECGs) using band-power (BP) feature analysis and machine learning.Methods: In this study, we proposed a novel ECG classification framework to differentiate fibrillation organisation levels. BP features were derived from surface ECGs and fed to a linear discriminant analysis classifier to predict fibrillation organisation level. Two datasets, single-channel ECGs of rat VF (n = 9) and 12-lead ECGs of human AF (n = 17), were used for model evaluation in a leave-one-out (LOO) manner.Results: The proposed method correctly predicted the organisation level from rat VF ECG with the sensitivity of 75%, specificity of 80%, and accuracy of 78%, and from clinical AF ECG with the sensitivity of 80%, specificity of 92%, and accuracy of 88%.Conclusion: Our proposed method can distinguish between AF/VF of different global organisation levels non-invasively from the ECG alone. This may aid in patient selection and guiding mechanism-directed tailored treatment strategies.

Journal article

Arnold AD, Shun-Shin MJ, Ali N, Keene D, Howard JP, Chow J-J, Qureshi NA, Koa-Wing M, Tanner M, Lefroy DC, Linton NWF, Ng FS, Lim PB, Peters NS, Kanagaratnam P, Francis DP, Whinnett ZIet al., 2021, Left ventricular activation time and pattern are preserved with both selective and non-selective his bundle pacing, Heart Rhythm O2, Vol: 2, Pages: 439-445, ISSN: 2666-5018

BackgroundHis bundle pacing (HBP) can be achieved in two ways: selective HBP (S-HBP), where the His bundle is captured alone, and non-selective HBP (NS-HBP), where local myocardium is also captured resulting a pre-excited ECG appearance.ObjectiveWe assessed the impact of this ventricular pre-excitation on left and right ventricular dys-synchrony.MethodsWe recruited patients who displayed both S-HBP and NS-HBP. We performed non-invasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern.Results20 patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5ms (95% confidence interval: -0.6 to -10.4, non-inferiority p<0.0001). NS-HBP did not prolong RVAT (4.3ms, -4.0 to 12.8, p=0.296) but did prolong QRS duration (QRSd, 22.1ms, 11.8 to 32.4, p = 0.0003). In patients with narrow intrinsic QRS (n=6), NS-HBP preserved LVAT (-2.9ms, -9.7 to 4.0, p=0.331) but prolonged QRS duration (31.4ms, 22.0 to 40.7, p=0.0003) and mean RVAT (16.8ms, -5.3 to 38.9, p=0.108) compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP.ConclusionCompared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dys-synchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients.

Journal article

Katritsis G, Luther V, Jamil-Copley S, Koa-Wing M, Qureshi N, Whinnett Z, Lim PB, Ng FS, Malcolme-Lawes L, Peters NS, Fudge M, Lim E, Linton NWF, Kanagaratnam Pet al., 2021, Postinfarct ventricular tachycardia substrate: Characterization and ablation of conduction channels using ripple mapping, Heart Rhythm, Vol: 18, Pages: 1682-1690, ISSN: 1547-5271

BackgroundConduction channels have been demonstrated within the postinfarct scar and seem to be co-located with the isthmus of ventricular tachycardia (VT). Mapping the local scar potentials (SPs) that define the conduction channels is often hindered by large far-field electrograms generated by healthy myocardium.ObjectiveThe purpose of this study was to map conduction channel using ripple mapping to categorize SPs temporally and anatomically. We tested the hypothesis that ablation of early SPs would eliminate the latest SPs without direct ablation.MethodsRipple maps of postinfarct scar were collected using the PentaRay (Biosense Webster) during normal rhythm. Maps were reviewed in reverse, and clusters of SPs were color-coded on the geometry, by timing, into early, intermediate, late, and terminal. Ablation was delivered sequentially from clusters of early SPs, checking for loss of terminal SPs as the endpoint.ResultsThe protocol was performed in 11 patients. Mean mapping time was 65 ± 23 minutes, and a mean 3050 ± 1839 points was collected. SP timing ranged from 98.1 ± 60.5 ms to 214.8 ± 89.8 ms post QRS peak. Earliest SPs were present at the border, occupying 16.4% of scar, whereas latest SPs occupied 4.8% at the opposing border or core. Analysis took 15 ± 10 minutes to locate channels and identify ablation targets. It was possible to eliminate latest SPs in all patients without direct ablation (mean ablation time 16.3 ± 11.1 minutes). No VT recurrence was recorded (mean follow-up 10.1 ± 7.4 months).ConclusionConduction channels can be located using ripple mapping to analyze SPs. Ablation at channel entrances can eliminate the latest SPs and is associated with good medium-term results.

Journal article

Falkenberg M, Coleman J, Dobson S, Hickey D, Terrill L, Ciacci A, Thomas B, Peters N, Sau A, Ng FS, Zhao J, Christensen Ket al., 2021, Identifying locations susceptible to micro-anatomical reentry using a spatial network representation of atrial fibre maps, Publisher: Cold Sprin Harbor Laboratory

Micro-anatomical reentry has been identified as a potential driver of atrial fibrillation (AF). In this paper, we introduce a novel computational method which aims to identify which atrial regions are most susceptible to micro-reentry. The approach, which considers the structural basis for micro-reentry only, is based on the premise that the accumulation of electrically insulating interstitial fibrosis can be modelled by simulating percolation-like phenomena on spatial networks. Our results suggest that at high coupling, where micro-reentry is rare, the micro-reentrant substrate is highly clustered in areas where the atrial walls are thin and have convex wall morphology. However, as transverse connections between fibres are removed, mimicking the accumulation of interstitial fibrosis, the substrate becomes less spatially clustered, and the bias to forming in thin, convex regions of the atria is reduced. Comparing our algorithm on image-based models with and without atrial fibre structure, we find that strong longitudinal fibre coupling can suppress the micro-reentrant substrate, whereas regions with disordered fibre orientations have an enhanced risk of micro-reentry. We suggest that with further development, these methods may have future potential for patient-specific risk stratification, taking a longitudinal view of the development of the micro-reentrant substrate. <h4>Author summary</h4> Atrial fibrillation (AF) is the most common abnormal heart rhythm, yet, despite extensive research, treatment success rates remain poor. In part, this is because there is an incomplete understanding of the mechanistic origin of AF. In this paper, we investigate one proposed mechanism of AF, the formation of “micro-reentrant circuits”, which can be thought of as a “short circuit”, forming when electrically insulating fibrosis (structural repair tissue) infiltrates the space between heart muscle cells. Previously, such circuits have been found i

Working paper

Kim M-Y, Coyle C, Sohaib DT-SA, Sikkel MB, Luther V, Leong KMW, Malcolme-Lawes L, Low B, Lim E, Todd MD, Fudge M, Wright IJ, Sandler B, Koa-Wing M, Ng FS, Qureshi NA, Whinnett ZI, Peters NS, Newcomb D, Wood C, Dhillon GS, Hunter RJ, Lim PB, Linton NF, Kanagaratnam Pet al., 2021, GANGLIONATED PLEXUS ABLATION TO PREVENT ATRIAL FIBRILLATION (GANGLIA-AF TRIAL), HEART RHYTHM, Vol: 18, Pages: 1632-1632, ISSN: 1547-5271

Journal article

Arnold AD, Shun-Shin MJ, Ali N, Keene D, Howard JP, Chow J-J, Qureshi NA, Koa-Wing M, Tanner M, Lefroy DC, Linton NWF, Ng FS, Lim PB, Peters NS, Kanagaratnam P, Francis DP, Whinnett ZIet al., 2021, Left ventricular activation time and pattern are preserved with both selective and nonselective His bundle pacing, Heart rhythm O2, Vol: 2, Pages: 439-445, ISSN: 2666-5018

<h4>Background</h4> His bundle pacing (HBP) can be achieved in 2 ways: selective HBP (S-HBP), where the His bundle is captured alone, and nonselective HBP (NS-HBP), where local myocardium is also captured, resulting a pre-excited electrocardiogram appearance. <h4>Objective</h4> We assessed the impact of this ventricular pre-excitation on left and right ventricular dyssynchrony. <h4>Methods</h4> We recruited patients who displayed both S-HBP and NS-HBP. We performed noninvasive epicardial electrical mapping for left and right ventricular activation time (LVAT and RVAT) and pattern. <h4>Results</h4> Twenty patients were recruited. In the primary analysis, the mean within-patient change in LVAT from S-HBP to NS-HBP was -5.5 ms (95% confidence interval: -0.6 to -10.4, noninferiority P < .0001). NS-HBP did not prolong RVAT (4.3 ms, -4.0 to 12.8, P = .296) but did prolong QRS duration (QRSd, 22.1 ms, 11.8 to 32.4, P = .0003). In patients with narrow intrinsic QRS (n = 6), NS-HBP preserved LVAT (-2.9 ms, -9.7 to 4.0, P = .331) but prolonged QRS duration (31.4 ms, 22.0 to 40.7, P = .0003) and mean RVAT (16.8 ms, -5.3 to 38.9, P = .108) compared to S-HBP. Activation pattern of the left ventricular surface was unchanged between S-HBP and NS-HBP, but NS-HBP produced early basal right ventricular activation that was not seen in S-HBP. <h4>Conclusion</h4> Compared to S-HBP, local myocardial capture during NS-HBP produces pre-excitation of the basal right ventricle resulting in QRS duration prolongation. However, NS-HBP preserves the left ventricular activation time and pattern of S-HBP. Left ventricular dyssynchrony is not an important factor when choosing between S-HBP and NS-HBP in most patients. Graphical abstract

Journal article

Jabbour R, Owen T, Pandey P, reinsch M, Wang B, King O, Couch L, Pantou D, Pitcher D, Chowdhury R, Pitoulis F, Handa B, Kit-Anan W, Perbellini F, myles R, Stuckey D, dunne M, Shanmuganathan M, Peters N, Ng FS, weinberger F, Terracciano C, smith G, Eschenhagen T, Harding Set al., 2021, In vivo grafting of large engineered heart tissue patches for cardiac repair, JCI Insight, Vol: 6, Pages: 1-13, ISSN: 2379-3708

Engineered heart tissue (EHT) strategies, by combining cells within a hydrogel matrix, may be anovel therapy for heart failure. EHTs restore cardiac function in rodent injury models, but more dataare needed in clinically relevant settings. Accordingly, an upscaled EHT patch (2.5 cm × 1.5 cm × 1.5mm) consisting of up to 20 million human induced pluripotent stem cell–derived cardiomyocytes(hPSC-CMs) embedded in a fibrin-based hydrogel was developed. A rabbit myocardial infarctionmodel was then established to test for feasibility and efficacy. Our data showed that hPSC-CMs inEHTs became more aligned over 28 days and had improved contraction kinetics and faster calciumtransients. Blinded echocardiographic analysis revealed a significant improvement in function ininfarcted hearts that received EHTs, along with reduction in infarct scar size by 35%. Vascularizationfrom the host to the patch was observed at week 1 and stable to week 4, but electrical couplingbetween patch and host heart was not observed. In vivo telemetry recordings and ex vivoarrhythmia provocation protocols showed that the patch was not pro-arrhythmic. In summary, EHTsimproved function and reduced scar size without causing arrhythmia, which may be due to the lackof electrical coupling between patch and host heart.

Journal article

Jenkins C, Ng FS, Sattler S, 2021, Establishment of a mouse model of systemic autoimmunity to study the role of autoimmunity in post-myocardial infarction cardiac electrophysiological remodelling, Publisher: WILEY, Pages: 316-316, ISSN: 0014-2980

Conference paper

Ng FS, Toman O, Petru J, Peichl P, Winkle RA, Reddy VY, Neuzil P, Mead RH, Qureshi NA, Whinnett ZI, Bourn DW, Shelton MB, Kautzner J, Sharma AD, Hocini M, Haïssaguerre M, Peters NS, Efimov IRet al., 2021, Novel low-voltage multiPulse therapy to terminate atrial fibrillation., JACC: Clinical Electrophysiology, Vol: 7, Pages: 988-999, ISSN: 2405-5018

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 [IQR]: 0.14 to 1.21 J) and voltage of 42.5 V (IQR: 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.

Journal article

Patel K, Li X, Quint J, Ware J, Peters N, Ng FSet al., 2021, Increasing adiposity and the presence of cardiometabolic morbidity is associated with increased Covid-19-related mortality: results from the UK Biobank, BMC Endocrine Disorders, Vol: 21, Pages: 1-6, ISSN: 1472-6823

Background: Although obesity, defined by body mass index (BMI), has been associated with a higher risk of hospitalisation and more severe course of illness in Covid-19 positive patients amongst the British population, it is unclear if this translates into increased mortality. Furthermore, given that BMI is an insensitive indicator of adiposity, the effect of adipose volume on Covid-19 outcomes is also unknown. Methods: We used the UK Biobank repository, which contains clinical and anthropometric data, and is linked to Public Health England Covid-19 healthcare records, to address our research question. We performed age- and sex- adjusted logistic regression and Chi-squared test to compute the odds for Covid-19-related mortality as a consequence of increasing BMI, other more sensitive indices of adiposity such as waist:hip ratio (WHR) and percent body fat, as well as concomitant cardiometabolic illness.Results: 13502 participants were tested for Covid-19 (mean age 70+8 years, 48.9% male). 1,582 tested positive (mean age 68+9 years, 52.8% male), of which 305 died (mean age 75+6 years, 65.5% male). Increasing adiposity was associated with higher odds for Covid-19-related mortality. For every unit increase in BMI, WHR and percent body fat, the odds of death amongst the Covid19-positive participants increased by 1.04 (95% CI 1.01-1.07), 10.71 (95% CI 1.57-73.06) and 1.03 (95% CI 1.01-1.05), respectively (all p<0.05). Referenced to Covid-19 positive participants with a normal weight (BMI 18.5-25kg/m2), Covid-19 positive participants with BMI>35kg/m2 had significantly higher odds of Covid-19-related death (OR 1.70, 95% CI 1.06-2.74, p<0.05). Covid-19-positive participants with metabolic (diabetes, hypertension, dyslipidaemia) or cardiovascular morbidity (atrial fibrillation, angina) also had higher odds of death.Conclusions: Anthropometric indices that are more sensitive to adipose volume and its distribution than BMI, as well as concurrent cardiometabolic illnes

Journal article

Mann I, Linton NWF, Coyle C, Howard JP, Fudge M, Lim E, Qureshi N, Koa-Wing M, Whinnett Z, Lim PB, Ng FS, Peters NS, Francis DP, Kanagaratnam Pet al., 2021, RETRO-MAPPING A New Approach to Activation Mapping in Persistent Atrial Fibrillation Reveals Evidence of Spatiotemporal Stability, CIRCULATION-ARRHYTHMIA AND ELECTROPHYSIOLOGY, Vol: 14, ISSN: 1941-3149

Journal article

Sekelj S, Sandler B, Johnston E, Pollock KG, Hill NR, Gordon J, Tsang C, Khan S, Ng FS, Farooqui Uet al., 2021, 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, Vol: 28, Pages: 598-605, 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

Sekelj S, Sandler B, Johnston E, Pollock KG, Hill NR, Gordon J, Tsang C, Khan S, Ng FS, Farooqui Uet al., 2021, Detecting undiagnosed atrial fibrillation in UK primary care: Validation of a machine learning prediction algorithm in a retrospective cohort study., Eur J Prev Cardiol, Vol: 28, Pages: 598-605

AIMS: To evaluate the ability of a machine learning algorithm to identify patients at high risk of atrial fibrillation in primary care. METHODS: A 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. RESULTS: Of 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. CONCLUSIONS: This 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

Chowdhury R, Debney M, Protti A, Handa B, Patel K, Lyon A, shah A, ng FS, Peters Net al., 2021, Rotigaptide Infusion for the First 7 Days After Myocardial Infarction–Reperfusion Reduced Late Complexity of Myocardial Architecture of the Healing Border-Zone and Arrhythmia Inducibility, Journal of the American Heart Association, Vol: 10, Pages: 1-18, ISSN: 2047-9980

BackgroundSurvivors of myocardial infarction are at increased risk of late ventricular arrhythmias, with infarct size and scar heterogeneity being key determinants of arrhythmic risk. Gap junctions facilitate the passage of small ions and morphogenic cell signaling between myocytes. We hypothesized that gap junctions enhancement during infarction–reperfusion modulates structural and electrophysiological remodeling and reduces late arrhythmogenesis.Methods and ResultsInfarction–reperfusion surgery was carried out in male Sprague‐Dawley rats followed by 7 days of rotigaptide or saline administration. The in vivo and ex vivo arrhythmogenicity was characterized by programmed electrical stimulation 3 weeks later, followed by diffusion‐weighted magnetic resonance imaging and Masson's trichrome histology. Three weeks after 7‐day postinfarction administration of rotigaptide, ventricular tachycardia/ventricular fibrillation was induced on programmed electrical stimulation in 20% and 53% of rats, respectively (rotigaptide versus control), resulting in reduction of arrhythmia score (3.2 versus 1.4, P=0.018), associated with the reduced magnetic resonance imaging parameters fractional anisotropy (fractional anisotropy: −5% versus −15%; P=0.062) and mean diffusivity (mean diffusivity: 2% versus 6%, P=0.042), and remodeling of the 3‐dimensional laminar structure of the infarct border zone with reduction of the mean (16° versus 19°, P=0.013) and the dispersion (9° versus 12°, P=0.015) of the myofiber transverse angle. There was no change in ECG features, spontaneous arrhythmias, or mortality.ConclusionsEnhancement of gap junctions function by rotigaptide administered during the early healing phase in reperfused infarction reduces later complexity of infarct scar morphology and programmed electrical stimulation–induced arrhythmias, and merits further exploration as a feasible and practicable intervention in the acute myocardial infarcti

Journal article

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