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
Year
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125 results found

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., 2021, Cycle Length Evaluation in Persistent Atrial Fibrillation Using Kernel Density Estimation to Identify Transient and Stable Rapid Atrial Activity, CARDIOVASCULAR ENGINEERING AND TECHNOLOGY, ISSN: 1869-408X

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

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

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

BACKGROUND: Conduction 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. OBJECTIVE: The 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. METHODS: Ripple 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. RESULTS: The 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). CONCLUSION: Conduction 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

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, 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

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

Katritsis G, Luther V, Cortez-Dias N, Carpinteiro L, de Sousa J, Lim PB, Whinnett Z, Ng FS, Koa-Wing M, Qureshi N, Chow A, Agarwal S, Jamil-Copley S, Peters NS, Linton N, Kanagaratnam Pet al., 2021, Electroanatomic characterization and ablation of scar-related isthmus sites supporting perimitral flutter, JACC: Clinical Electrophysiology, Vol: 7, Pages: 578-590, ISSN: 2405-5018

ObjectivesThe authors reviewed 3-dimensional electroanatomic maps of perimitral flutter to identify scar-related isthmuses and determine their effectiveness as ablation sites.BackgroundPerimitral flutter is usually treated by linear ablation between the left lower pulmonary vein and mitral annulus. Conduction block can be difficult to achieve, and recurrences are common.MethodsPatients undergoing atrial tachycardia ablation using CARTO3 (Biosense Webster Inc., Irvine, California) were screened from 4 centers. Patients with confirmed perimitral flutter were reviewed for the presence of scar-related isthmuses by using CARTO3 with the ConfiDense and Ripple Mapping modules.ResultsConfirmed perimitral flutter was identified in 28 patients (age 65.2 ± 8.1 years), of whom 26 patients had prior atrial fibrillation ablation. Scar-related isthmus ablation was performed in 12 of 28 patients. Perimitral flutter was terminated in all following correct identification of a scar-related isthmus using ripple mapping. The mean scar voltage threshold was 0.11 ± 0.05 mV. The mean width of scar-related isthmuses was 8.9 ± 3.5 mm with a conduction speed of 31.8 ± 5.5 cm/s compared to that of normal left atrium of 71.2 ± 21.5 cm/s (p < 0.0001). Empirical, anatomic ablation was performed in 16 of 28, with termination in 10 of 16 (63%; p = 0.027). Significantly less ablation was required for critical isthmus ablation compared to empirical linear lesions (11.4 ± 5.3 min vs. 26.2 ± 17.1 min; p = 0.0004). All 16 cases of anatomic ablation were reviewed with ripple mapping, and 63% had scar-related isthmus.ConclusionsPerimitral flutter is usually easy to diagnose but can be difficult to ablate. Ripple mapping is highly effective at locating the critical isthmus maintaining the tachycardia and avoiding anatomic ablation lines. This approach has a higher termination rate with less radiofrequency ablation required.

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., 2021, Ventricular fibrillation mechanism and global fibrillatory organisation are determined by gap junction coupling and fibrosis pattern, Cardiovascular Research, Vol: 117, Pages: 1078-1090, 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

Leong KMW, Ng FS, Shun-Shin MJ, Koa-Wing M, Qureshi N, Whinnett Z, Linton NF, Lefroy D, Francis DP, Harding SE, Davies DW, Peter NS, Lim PB, Behr E, Lambiase PD, Varnava A, Kanagaratnam Pet al., 2021, Non-invasive detection of exercise-induced cardiac conduction abnormalities in sudden cardiac death survivors in the inherited cardiac conditions, EUROPACE, Vol: 23, Pages: 305-312, ISSN: 1099-5129

Journal article

Forte E, Panahi M, Baxan N, Ng FS, Boyle JJ, Branca J, Bedard O, Hasham MG, Benson L, Harding SE, Rosenthal N, Sattler Set al., 2021, Type 2 MI 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, Vol: 25, Pages: 229-243, 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 is used for its cardiac effects in a variety of different dosing regimens with high doses causing acute cardiomyocyte necrosis. To assess whether isoproterenol-induced cardiomyocyte necrosis triggers an adaptive immune response against the heart, we treated C57BL/6J mice with a single intraperitoneal injection of 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

Moscoso Costa F, Ng FS, 2021, Oxidative stress and atrial fibrillation - association or causation?, Revista Portuguesa de Cardiología, Vol: 40, Pages: 11-12, ISSN: 0870-2551

Journal article

Forte E, Perkins B, Sintou A, Kallkat HS, Papanikolaou A, Jenkins C, Alsubaie M, Chowdhury RA, Duffy TM, Skelly DA, Branca J, Bellahcene M, Schneider M, Harding S, Furtado MB, Ng FS, Hasham MG, Rosenthal N, Sattler Set al., 2020, Cross-priming dendritic cells exacerbate immunopathology after ischemic tissue damage in the heart, Circulation, Vol: 143, Pages: 821-836, ISSN: 0009-7322

Background: Ischemic heart disease is a leading cause of heart failure and despite advanced therapeutic options, morbidity and mortality rates remain high. Although acute inflammation in response to myocardial cell death has been extensively studied, subsequent adaptive immune activity and anti-heart autoimmunity may also contribute to the development of HF. After ischemic injury to the myocardium, dendritic cells (DC) respond to cardiomyocyte necrosis, present cardiac antigen to T cells and potentially initiate a persistent autoimmune response against the heart. Cross-priming DC have the ability to activate both CD4+ helperand CD8+ cytotoxic T cells in response to necrotic cells and may thus be crucial players in exacerbating autoimmunity targeting the heart. This study investigates a role for cross priming DC in post-MI myocardial impairment through presentation of self-antigen fromnecrotic cardiomyocytes to cytotoxic CD8+ T cells.Methods: We induced type-2 myocardial infarction (MI)-like ischemic injury in the heart by treatment with a single high dose of the beta-adrenergic agonist isoproterenol. We characterized the DC population in the heart and mediastinal lymph nodes and analyzed long term cardiac immunopathology and functional decline in wild type and Clec9a-depleted mice lacking DC cross-priming function.Results: A diverse DC population, including cross-priming DC, is present in the heart and activated after ischemic injury. Clec9a -/- mice deficient in DC cross-priming are protected from long-term immune-mediated myocardial damage and decline of cardiac function, likely dueto dampened activation of cytotoxic CD8+ T cells.Conclusion: Activation of cytotoxic CD8+ T cells by cross-priming DC contributes to exacerbation of post-ischemic inflammatory damage of the myocardium and corresponding decline in cardiac function. Importantly, this provides novel therapeutic targets to prevent immune-mediated worsening of post-ischemic HF.

Journal article

Pollock KG, Sekelj S, Johnston E, Sandler B, Hill NR, Ng FS, Khan S, Nassar A, Farooqui Uet al., 2020, Application of a machine learning algorithm for detection of atrial fibrillation in secondary care, IJC HEART & VASCULATURE, Vol: 31

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 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, Vol: 31, Pages: 2964-2974, ISSN: 1045-3873

AimsA prolonged PR interval may adversely affect ventricular filling and, therefore, cardiac function. AV delay can be corrected using right ventricular pacing (RVP), but this induces ventricular dyssynchrony, itself harmful. Therefore, in intermittent heart block, pacing avoidance algorithms are often implemented. We tested His‐bundle pacing (HBP) as an alternative.MethodsOutpatients with a long PR interval (>200 ms) and intermittent need for ventricular pacing were recruited. We measured within‐patient differences in high‐precision hemodynamics between AV‐optimized RVP and HBP, as well as a pacing avoidance algorithm (Managed Ventricular Pacing [MVP]).ResultsWe recruited 18 patients. Mean left ventricular ejection fraction was 44.3 ± 9%. Mean intrinsic PR interval was 266 ± 42 ms and QRS duration was 123 ± 29 ms. RVP lengthened QRS duration (+54 ms, 95% CI 42–67 ms, p < .0001) while HBP delivered a shorter QRS duration than RVP (−56 ms, 95% CI −67 to −46 ms, p < .0001). HBP did not increase QRS duration (−2 ms, 95% CI −8 to 13 ms, p = .6). HBP improved acute systolic blood pressure by mean of 5.0 mmHg (95% CI 2.8–7.1 mmHg, p < .0001) compared to RVP and by 3.5 mmHg (95% CI 1.9–5.0 mmHg, p = .0002) compared to the pacing avoidance algorithm. There was no significant difference in hemodynamics between RVP and ventricular pacing avoidance (p = .055).ConclusionsHBP provides better acute cardiac function than pacing avoidance algorithms and RVP, in patients with prolonged PR intervals. HBP allows normalization of prolonged AV delays (unlike pacing avoidance) and does not cause ventricular dyssynchrony (unlike RVP). Clinical trials may be justified to assess whether these acute

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, Vol: 319, Pages: H1008-H1020, 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

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., Cardiovascular Digital Health Journal, 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 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

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

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