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  • Journal article
    Mann I, Sandler B, Linton N, Kanagaratnam Pet al., 2018,

    Drivers of Atrial Fibrillation: Theoretical Considerations and Practical Concerns

    , ARRHYTHMIA & ELECTROPHYSIOLOGY REVIEW, Vol: 7, Pages: 49-54, ISSN: 2050-3369
  • Journal article
    Houston C, Ng FS, Dupont E, 2018,

    Letter by Houston et al regarding article, "Localized Optogenetic Targeting of Rotors in Atrial Cardiomyocyte Monolayers"

    , Circulation: Arrhythmia and Electrophysiology, Vol: 11, Pages: e006118-e006118, ISSN: 1941-3084
  • Journal article
    Machuki JO, Zhang HY, Harding SE, Sun Het al., 2018,

    Molecular pathways of oestrogen receptors and -adrenergic receptors in cardiac cells: Recognition of their similarities, interactions and therapeutic value

    , ACTA PHYSIOLOGICA, Vol: 222, ISSN: 1748-1708

    Oestrogen receptors (ERs) and β‐adrenergic receptors (βARs) play important roles in the cardiovascular system. Moreover, these receptors are expressed in cardiac myocytes and vascular tissues. Numerous experimental observations support the hypothesis that similarities and interactions exist between the signalling pathways of ERs (ERα, ERβ and GPR30) and βARs (β1AR, β2AR and β3AR). The recently discovered oestrogen receptor GPR30 shares structural features with the βARs, and this forms the basis for the interactions and functional overlap. GPR30 possesses protein kinase A (PKA) phosphorylation sites and PDZ binding motifs and interacts with A‐kinase anchoring protein 5 (AKAP5), all of which enable its interaction with the βAR pathways. The interactions between ERs and βARs occur downstream of the G‐protein‐coupled receptor, through the Gαs and Gαi proteins. This review presents an up‐to‐date description of ERs and βARs and demonstrates functional synergism and interactions among these receptors in cardiac cells. We explore their signalling cascades and the mechanisms that orchestrate their interactions and propose new perspectives on the signalling patterns for the GPR30 based on its structural resemblance to the βARs. In addition, we explore the relevance of these interactions to cell physiology, drugs (especially β‐blockers and calcium channel blockers) and cardioprotection. Furthermore, a receptor‐independent mechanism for oestrogen and its influence on the expression of βARs and calcium‐handling proteins are discussed. Finally, we highlight promising therapeutic avenues that can be derived from the shared pathways, especially the phosphatidylinositol‐3‐OH kinase (PI3K/Akt) pathway.

  • Journal article
    Luther V, Qureshi N, Lim PB, Koa-Wing M, Jamil-Copley S, Ng FS, Whinnett Z, Davies DW, Peters NS, Kanagaratnam P, Linton Net al., 2018,

    Isthmus sites identified by Ripple Mapping are usually anatomically stable: A novel method to guide atrial substrate ablation?

    , Journal of Cardiovascular Electrophysiology, Vol: 29, Pages: 404-411, ISSN: 1045-3873

    BACKGROUND: Postablation reentrant ATs depend upon conducting isthmuses bordered by scar. Bipolar voltage maps highlight scar as sites of low voltage, but the voltage amplitude of an electrogram depends upon the myocardial activation sequence. Furthermore, a voltage threshold that defines atrial scar is unknown. We used Ripple Mapping (RM) to test whether these isthmuses were anatomically fixed between different activation vectors and atrial rates. METHODS: We studied post-AF ablation ATs where >1 rhythm was mapped. Multipolar catheters were used with CARTO Confidense for high-density mapping. RM visualized the pattern of activation, and the voltage threshold below which no activation was seen. Isthmuses were characterized at this threshold between maps for each patient. RESULTS: Ten patients were studied (Map 1 was AT1; Map 2: sinus 1/10, LA paced 2/10, AT2 with reverse CS activation 3/10; AT2 CL difference 50 ± 30 ms). Point density was similar between maps (Map 1: 2,589 ± 1,330; Map 2: 2,214 ± 1,384; P  =  0.31). RM activation threshold was 0.16 ± 0.08 mV. Thirty-one isthmuses were identified in Map 1 (median 3 per map; width 27 ± 15 mm; 7 anterior; 6 roof; 8 mitral; 9 septal; 1 posterior). Importantly, 7 of 31 (23%) isthmuses were unexpectedly identified within regions without prior ablation. AT1 was treated following ablation of 11/31 (35%) isthmuses. Of the remaining 20 isthmuses, 14 of 16 isthmuses (88%) were consistent between the two maps (four were inadequately mapped). Wavefront collision caused variation in low voltage distribution in 2 of 16 (12%). CONCLUSIONS: The distribution of isthmuses and nonconducting tissue within the ablated left atrium, as defined by RM, appear concordant between rhythms. This could guide a substrate ablative approach.

  • Journal article
    Zaman JAB, Sauer WH, Alhusseini MI, Baykaner T, Borne RT, Kowalewski CAB, Busch S, Zei PC, Park S, Viswanathan MN, Wang PJ, Brachmann J, Krummen DE, Miller JM, Rappel WJ, Narayan SM, Peters NSet al., 2018,

    Identification and characterization of sites where persistent atrial fibrillation is terminated by localized ablation

    , Circulation: Arrhythmia and Electrophysiology, Vol: 11, ISSN: 1941-3084

    BACKGROUND: The mechanisms by which persistent atrial fibrillation (AF) terminates via localized ablation are not well understood. To address the hypothesis that sites where localized ablation terminates persistent AF have characteristics identifiable with activation mapping during AF, we systematically examined activation patterns acquired only in cases of unequivocal termination by ablation. METHODS AND RESULTS: We recruited 57 patients with persistent AF undergoing ablation, in whom localized ablation terminated AF to sinus rhythm or organized tachycardia. For each site, we performed an offline analysis of unprocessed unipolar electrograms collected during AF from multipolar basket catheters using the maximum -dV/dt assignment to construct isochronal activation maps for multiple cycles. Additional computational modeling and phase analysis were used to study mechanisms of map variability. At all sites of AF termination, localized repetitive activation patterns were observed. Partial rotational circuits were observed in 26 of 57 (46%) cases, focal patterns in 19 of 57 (33%), and complete rotational activity in 12 of 57 (21%) cases. In computer simulations, incomplete segments of partial rotations coincided with areas of slow conduction characterized by complex, multicomponent electrograms, and variations in assigning activation times at such sites substantially altered mapped mechanisms. CONCLUSIONS: Local activation mapping at sites of termination of persistent AF showed repetitive patterns of rotational or focal activity. In computer simulations, complete rotational activation sequence was observed but was sensitive to assignment of activation timing particularly in segments of slow conduction. The observed phenomena of repetitive localized activation and the mechanism by which local ablation terminates putative AF drivers require further investigation.

  • Journal article
    von Rosenberg W, Chanwimalueang T, Goverdovsky V, Peters NS, Papavassiliou C, Mandic DPet al., 2017,

    Hearables: feasibility of recording cardiac rhythms from head and in-ear locations

    , Royal Society Open Science, Vol: 4, ISSN: 2054-5703

    Mobile technologies for the recording of vital signs and neural signals are envisaged to underpin the operation of future health services. For practical purposes, unobtrusive devices are favoured, such as those embedded in a helmet or incorporated onto an earplug. However, these locations have so far been underexplored, as the comparably narrow neck impedes the propagation of vital signals from the torso to the head surface. To establish the principles behind electrocardiogram (ECG) recordings from head and ear locations, we first introduce a realistic three-dimensional biophysics model for the propagation of cardiac electric potentials to the head surface, which demonstrates the feasibility of head-ECG recordings. Next, the proposed biophysics propagation model is verified over comprehensive real-world experiments based on head- and in-ear-ECG measurements. It is shown both that the proposed model is an excellent match for the recordings, and that the quality of head- and ear-ECG is sufficient for a reliable identification of the timing and shape of the characteristic P-, Q-, R-, S- and T-waves within the cardiac cycle. This opens up a range of new possibilities in the identification and management of heart conditions, such as myocardial infarction and atrial fibrillation, based on 24/7 continuous in-ear measurements. The study therefore paves the way for the incorporation of the cardiac modality into future ‘hearables’, unobtrusive devices for health monitoring.

  • Journal article
    Leong KMW, chow J-J, Ng FS, Falaschetti E, Qureshi N, Koa-Wing M, Linton N, Whinnett Z, Lefroy D, Davies DW, Lim PB, Peters N, Kanagaratnam P, Varnava Aet al., 2017,

    Comparison of the Prognostic Usefulness of the European Society of Cardiology and American Heart Association/American College of Cardiology Foundation Risk Stratification Systems for Patients With Hypertrophic Cardiomyopathy

    , American Journal of Cardiology, Vol: 121, Pages: 349-355, ISSN: 0002-9149

    Implantable cardio-defibrillators (ICDs) have proven benefit in preventing sudden cardiac death (SCD) in hypertrophic cardiomyopathy (HC), making risk stratification essential. Data on the predictive accuracy on the European Society of Cardiology (ESC) risk scoring system has been conflicting. We independently evaluated the ESC risk scoring system in our cohort of HC patients from a large tertiary centre and compared this to previous guidance by the American College of Cardiology Foundation and Heart Association (ACCF/AHA). Risk factor profiles, 5-year SCD risk estimates and ICD recommendations as defined by the ACCF/AHA and ESC guidelines, were retrospectively ascertained for 288 HC patients with and without SCD or equivalent events at our centre. In the SCD group (n=14), a significantly higher proportion of patients would not have met the criteria for an ICD implant using the ESC scoring algorithm than ACCF/AHA guidance (43%vs7%, p=0.029). In those without SCD events (n=274), a larger proportion of individuals not requiring an ICD was identified using the ESC risk score model compared to the ACCF/AHA model (82%vs57%; p<0.0001). Based on risk stratification criteria alone, 5 more individuals with a previously aborted SCD event would not have received an ICD with the ESC risk model than the ACCF/AHA risk model. In conclusion, we found that the current ESC scoring system potentially leaves more high-risk patients unprotected from sudden death in our cohort of patients.

  • Journal article
    Leong KMW, Ng FS, Roney C, Cantwell C, Shun-Shin M, Linton N, Whinnett Z, Lefroy D, Davies DW, Harding S, Lim PB, Francis D, Peters N, Varnava A, Kanagaratnam Pet al., 2017,

    Repolarization abnormalities unmasked with exercise in sudden cardiac death survivors with structurally normal hearts

    , Journal of Cardiovascular Electrophysiology, Vol: 29, Pages: 115-126, ISSN: 1045-3873

    BACKGROUND: Models of cardiac arrhythmogenesis predict that non-uniformity in repolarization and/or depolarization promotes ventricular fibrillation and is modulated by autonomic tone, but this is difficult to evaluate in patients. We hypothesize that such spatial heterogeneities would be detected by non-invasive ECG imaging (ECGi) in sudden cardiac death (SCD) survivors with structurally normal hearts under physiological stress. METHODS: ECGi was applied to 11 SCD survivors, 10 low-risk Brugada Syndrome patients (BrS) and 10 controls undergoing exercise treadmill testing. ECGi provides whole heart activation maps and > 1200 unipolar electrograms over the ventricular surface from which global dispersion of activation recovery interval (ARI) and regional delay in conduction were determined. These were used as surrogates for spatial heterogeneities in repolarization and depolarization. Surface ECG markers of dispersion (QT and Tpeak-end intervals) were also calculated for all patients for comparison. RESULTS: Following exertion, the SCD group demonstrated the largest increase in ARI dispersion compared to BrS and control groups (13±8 ms vs 4±7 ms vs 4±5 ms; p = 0.009), with baseline dispersion being similar in all groups. In comparison, surface ECG markers of dispersion of repolarisation were unable to discriminate between the groups at baseline or following exertion. Spatial heterogeneities in conduction were also present following exercise but were not significantly different between SCD survivors and the other groups. CONCLUSION: Increased dispersion of repolarization is apparent during physiological stress in SCD survivors and is detectable with ECGi but not with standard ECG parameters. The electrophysiological substrate revealed by ECGi could be the basis of alternative risk-stratification techniques. This article is protected by copyright. All rights reserved.

  • Journal article
    Leong KMW, Ng FS, yao C, Roney C, Linton N, Whinnett Z, lefroy D, Davies DW, Lim PB, Harding S, Peters N, Kanagaratnam P, Varnava Aet al., 2017,

    ST-Elevation Magnitude Correlates With Right Ventricular Outflow Tract Conduction Delay in Type I Brugada ECG

    , Circulation: Arrhythmia and Electrophysiology, Vol: 10, ISSN: 1941-3084

    Background: The substrate location and underlying electrophysiological mechanisms that contribute to the characteristic ECG pattern of Brugada syndrome (BrS) are still debated. Using noninvasive electrocardiographical imaging, we studied whole heart conduction and repolarization patterns during ajmaline challenge in BrS individuals.Methods and Results: A total of 13 participants (mean age, 44±12 years; 8 men), 11 concealed patients with type I BrS and 2 healthy controls, underwent an ajmaline infusion with electrocardiographical imaging and ECG recordings. Electrocardiographical imaging activation recovery intervals and activation timings across the right ventricle (RV) body, outflow tract (RVOT), and left ventricle were calculated and analyzed at baseline and when type I BrS pattern manifested after ajmaline infusion. Peak J-ST point elevation was calculated from the surface ECG and compared with the electrocardiographical imaging–derived parameters at the same time point. After ajmaline infusion, the RVOT had the greatest increase in conduction delay (5.4±2.8 versus 2.0±2.8 versus 1.1±1.6 ms; P=0.007) and activation recovery intervals prolongation (69±32 versus 39±29 versus 21±12 ms; P=0.0005) compared with RV or left ventricle. In controls, there was minimal change in J-ST point elevation, conduction delay, or activation recovery intervals at all sites with ajmaline. In patients with BrS, conduction delay in RVOT, but not RV or left ventricle, correlated to the degree of J-ST point elevation (Pearson R, 0.81; P<0.001). No correlation was found between J-ST point elevation and activation recovery intervals prolongation in the RVOT, RV, or left ventricle.Conclusions: Magnitude of ST (J point) elevation in the type I BrS pattern is attributed to degree of conduction delay in the RVOT and not prolongation in repolarization time.

  • Journal article
    Chow A, Stuckey DJ, Kidher E, Rocco M, Jabbour RJ, Mansfield CA, Darzi A, Harding SE, Stevens MM, Athanasiou Tet al., 2017,

    Human Induced Pluripotent Stem Cell-Derived Cardiomyocyte Encapsulating Bioactive Hydrogels Improve Rat Heart Function Post Myocardial Infarction.

    , Stem Cell Reports, Vol: 9, Pages: 1415-1422, ISSN: 2213-6711

    Tissue engineering offers an exciting possibility for cardiac repair post myocardial infarction. We assessed the effects of combined polyethylene glycol hydrogel (PEG), human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM), and erythropoietin (EPO) therapy in a rat model of myocardial infarction. PEG with/out iPSC-CMs and EPO; iPSC-CMs in saline; or saline alone was injected into infarcted hearts shortly after infarction. Injection of almost any combination of the therapeutics limited acute elevations in chamber volumes. After 10 weeks, attenuation of ventricular remodeling was identified in all groups that received PEG injections, while ejection fractions were significantly increased in the gel-EPO, cell, and gel-cell-EPO groups. In all treatment groups, infarct thickness was increased and regions of muscle were identified within the scar. However, no grafted cells were detected. Hence, iPSC-CM-encapsulating bioactive hydrogel therapy can improve cardiac function post myocardial infarction and increase infarct thickness and muscle content despite a lack of sustained donor-cell engraftment.

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