Publications
14 results found
Kim MY, Nesbitt J, Koutsoftidis S, et al., 2023, Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high frequency stimulation, EP Europace, Vol: 25, Pages: 726-738, 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.
Sau A, Ibrahim S, Ahmed A, et al., 2022, Artificial intelligence-enabled electrocardiogram to distinguish cavotricuspid isthmus dependence from other atrial tachycardia mechanisms, European Heart Journal – Digital Health, Vol: 3, Pages: 405-414, ISSN: 2634-3916
Aims:Accurately determining atrial arrhythmia mechanisms from a 12-lead electrocardiogram (ECG) can be challenging. Given the high success rate of cavotricuspid isthmus (CTI) ablation, identification of CTI-dependent typical atrial flutter (AFL) is important for treatment decisions and procedure planning. We sought to train a convolutional neural network (CNN) to classify CTI-dependent AFL vs. non-CTI dependent atrial tachycardia (AT), using data from the invasive electrophysiology (EP) study as the gold standard.Methods and results:We trained a CNN on data from 231 patients undergoing EP studies for atrial tachyarrhythmia. A total of 13 500 five-second 12-lead ECG segments were used for training. Each case was labelled CTI-dependent AFL or non-CTI-dependent AT based on the findings of the EP study. The model performance was evaluated against a test set of 57 patients. A survey of electrophysiologists in Europe was undertaken on the same 57 ECGs. The model had an accuracy of 86% (95% CI 0.77–0.95) compared to median expert electrophysiologist accuracy of 79% (range 70–84%). In the two thirds of test set cases (38/57) where both the model and electrophysiologist consensus were in agreement, the prediction accuracy was 100%. Saliency mapping demonstrated atrial activation was the most important segment of the ECG for determining model output.Conclusion:We describe the first CNN trained to differentiate CTI-dependent AFL from other AT using the ECG. Our model matched and complemented expert electrophysiologist performance. Automated artificial intelligence-enhanced ECG analysis could help guide treatment decisions and plan ablation procedures for patients with organized atrial arrhythmias.
Li X, Shi X, Handa BS, et 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.
Jabbour R, Owen T, Pandey P, et 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.
Chowdhury R, Debney M, Protti A, et 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
Handa B, Li X, Baxan N, et 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
Brook J, Kim M-Y, Koutsoftidis S, et 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.
Ng FS, Handa B, Li X, et 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.
Handa BS, Li X, Aras KK, et 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: 1941-3084
Handa B, Li X, Aras KK, et 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).
Li X, Handa BS, Peters NS, et 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 % .
Li X, Roney C, Handa B, et 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.
Handa B, Lawal S, Wright IJ, et al., 2019, Interventricular differences in action potential duration restitution contribute to dissimilar ventricular rhythms in ex vivo perfused hearts, Frontiers in Cardiovascular Medicine, Vol: 6, ISSN: 2297-055X
Background: Dissimilar ventricular rhythms refer to the occurrence of different ventricular tachyarrhythmias in the right and left ventricles or different rates of the same tachyarrhythmia in the two ventricles.Objective: We investigated the inducibility of dissimilar ventricular rhythms, their underlying mechanisms, and the impact of anti-arrhythmic drugs (lidocaine and amiodarone) on their occurrence.Methods: Ventricular tachyarrhythmias were induced with burst pacing in 28 Langendorff-perfused Sprague Dawley rat hearts (14 control, 8 lidocaine, 6 amiodarone) and bipolar electrograms recorded from the right and left ventricles. Fourteen (6 control, 4 lidocaine, 4 amiodarone) further hearts underwent optical mapping of transmembrane voltage to study interventricular electrophysiological differences and mechanisms of dissimilar rhythms.Results: In control hearts, dissimilar ventricular rhythms developed in 8/14 hearts (57%). In lidocaine treated hearts, there was a lower cycle length threshold for developing dissimilar rhythms, with 8/8 (100%) hearts developing dissimilar rhythms in comparison to 0/6 in the amiodarone group. Dissimilar ventricular tachycardia (VT) rates occurred at longer cycle lengths with lidocaine vs. control (57.1 ± 7.9 vs. 36.6 ± 8.4 ms, p < 0.001). The ratio of LV:RV VT rate was greater in the lidocaine group than control (1.91 ± 0.30 vs. 1.76 ± 0.36, p < 0.001). The gradient of the action potential duration (APD) restitution curve was shallower in the RV compared with LV (Control - LV: 0.12 ± 0.03 vs RV: 0.002 ± 0.03, p = 0.015), leading to LV-to-RV conduction block during VT.Conclusion: Interventricular differences in APD restitution properties likely contribute to the occurrence of dissimilar rhythms. Sodium channel blockade with lidocaine increases the likelihood of dissimilar ventricular rhythms.
Handa BS, Roney CH, Houston C, et al., 2018, Analytical approaches for myocardial fibrillation signals, Computers in Biology and Medicine, Vol: 102, Pages: 315-326, ISSN: 0010-4825
Atrial and ventricular fibrillation are complex arrhythmias, and their underlying mechanisms remain widely debated and incompletely understood. This is partly because the electrical signals recorded during myocardial fibrillation are themselves complex and difficult to interpret with simple analytical tools. There are currently a number of analytical approaches to handle fibrillation data. Some of these techniques focus on mapping putative drivers of myocardial fibrillation, such as dominant frequency, organizational index, Shannon entropy and phase mapping. Other techniques focus on mapping the underlying myocardial substrate sustaining fibrillation, such as voltage mapping and complex fractionated electrogram mapping. In this review, we discuss these techniques, their application and their limitations, with reference to our experimental and clinical data. We also describe novel tools including a new algorithm to map microreentrant circuits sustaining fibrillation.
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