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  • Journal article
    Calkins H, Hindricks G, Cappato R, Kim Y-H, Saad EB, Aguinaga L, Akar JG, Badhwar V, Brugada J, Camm J, Chen P-S, Chen S-A, Chung MK, Nielsen JC, Curtis AB, Davies DW, Day JD, d'Avila A, de Groot NMSN, Di Biase L, Duytschaever M, Edgerton JR, Ellenbogen KA, Ellinor PT, Ernst S, Fenelon G, Gerstenfeld EP, Haines DE, Haissaguerre M, Helm RH, Hylek E, Jackman WM, Jalife J, Kalman JM, Kautzner J, Kottkamp H, Kuck KH, Kumagai K, Lee R, Lewalter T, Lindsay BD, Macle L, Mansour M, Marchlinski FE, Michaud GF, Nakagawa H, Natale A, Nattel S, Okumura K, Packer D, Pokushalov E, Reynolds MR, Sanders P, Scanavacca M, Schilling R, Tondo C, Tsao H-M, Verma A, Wilber DJ, Yamane Tet al., 2017,

    2017 HRS/EHRA/ECAS/APHRS/SOLAECE expert consensus statement on catheter and surgical ablation of atrial fibrillation

    , EP-Europace, Vol: 20, Pages: E1-E160, ISSN: 1099-5129
  • Journal article
    Leong KMW, Ng FS, Patil S, Lim PBet al., 2017,

    An electrocardiogram opinion from an National Health Service walk-in centre

    , Emergency Medicine Journal, Vol: 34, Pages: 631-632, ISSN: 1472-0205
  • Journal article
    Sikkel MB, Francis DP, Howard J, Gordon F, Rowlands C, Peters NS, Lyon AR, Harding SE, MacLeod KTet al., 2017,

    Hierarchical statistical techniques are necessary to draw reliable conclusions from analysis of isolated cardiomyocyte studies

    , Cardiovascular Research, Vol: 113, Pages: 1743-1752, ISSN: 1755-3245

    AimsIt is generally accepted that post-MI heart failure (HF) changes a variety of aspects of sarcoplasmic reticular Ca2+ fluxes but for some aspects there is disagreement over whether there is an increase or decrease. The commonest statistical approach is to treat data collected from each cell as independent, even though they are really clustered with multiple likely similar cells from each heart. In this study, we test whether this statistical assumption of independence can lead the investigator to draw conclusions that would be considered erroneous if the analysis handled clustering with specific statistical techniques (hierarchical tests).Methods and resultsCa2+ transients were recorded in cells loaded with Fura-2AM and sparks were recorded in cells loaded with Fluo-4AM. Data were analysed twice, once with the common statistical approach (assumption of independence) and once with hierarchical statistical methodologies designed to allow for any clustering. The statistical tests found that there was significant hierarchical clustering. This caused the common statistical approach to underestimate the standard error and report artificially small P values. For example, this would have led to the erroneous conclusion that time to 50% peak transient amplitude was significantly prolonged in HF.Spark analysis showed clustering, both within each cell and also within each rat, for morphological variables. This means that a three-level hierarchical model is sometimes required for such measures. Standard statistical methodologies, if used instead, erroneously suggest that spark amplitude is significantly greater in HF and spark duration is reduced in HF.ConclusionCa2+ fluxes in isolated cardiomyocytes show so much clustering that the common statistical approach that assumes independence of each data point will frequently give the false appearance of statistically significant changes. Hierarchical statistical methodologies need a little more effort, but are necessary for relia

  • Journal article
    Sau A, Sikkel MB, Luther V, Wright I, Guerrero F, Koa-Wing M, Lefroy D, Linton N, Qureshi N, Whinnett Z, Lim PB, Kanagaratnam P, Peters NS, Davies DWet al., 2017,

    The sawtooth EKG pattern of typical atrial flutter is not related to slow conduction velocity at the cavotricuspid isthmus.

    , Journal of Cardiovascular Electrophysiology, Vol: 28, Pages: 1445-1453, ISSN: 1045-3873

    INTRODUCTION: We hypothesized that very high density mapping of typical atrial flutter (AFL) would facilitate a more complete understanding of its circuit. Such very high density mapping was performed with the Rhythmia mapping system using its 64 electrode basket catheter. METHODS AND RESULTS: Data were acquired from 13 patients in AFL. Functional anatomy of the right atrium (RA) was readily identified during mapping including the Crista Terminalis and Eustachian ridge. The leading edge of the activation wavefront was identified without interruption and its conduction velocity (CV) calculated. CV was not different at the cavotricuspid isthmus (CTI) compared to the remainder of the RA (1.02 vs. 1.03 m/s, p = 0.93). The sawtooth pattern of the surface EKG flutter waves were compared to the position of the dominant wavefront. The downslope of the surface EKG flutter waves represented on average, 73% ± 9% of the total flutter cycle length. During the downslope the activation wavefront travelled significantly further than during the upslope (182 ± 21 ms vs. 68 ± 29 ms, p < 0.0001) with no change in conduction velocity between the two phases (0.88 vs. 0.91 m/s, p = 0.79). CONCLUSION: CV at the CTI is not slower than other RA regions during typical AFL. The gradual downslope of the sawtooth EKG is not due to slow conduction at the CTI suggesting that success of ablation at this site relates to anatomical properties rather than presence of a "slow isthmus". This article is protected by copyright. All rights reserved.

  • Journal article
    Perbellini F, Watson SA, Scigliano M, Alayoubi S, Tkach S, Bardi I, Quaife N, Kane C, Dufton NP, Simon A, Sikkel MB, Faggian G, Randi AM, Gorelik J, Harding S, Terracciano CMNet al., 2017,

    Investigation of cardiac fibroblasts using myocardial slices

    , Cardiovascular Research, Vol: 114, Pages: 77-89, ISSN: 1755-3245

    AimsCardiac fibroblasts (CFs) are considered the principal regulators of cardiac fibrosis. Factors that influence CF activity are difficult to determine. When isolated and cultured in vitro, CFs undergo rapid phenotypic changes including increased expression of α-SMA. Here we describe a new model to study CFs and their response to pharmacological and mechanical stimuli using in vitro cultured mouse, dog and human myocardial slices.Methods and resultsUnloading of myocardial slices induced CF proliferation without α-SMA expression up to 7 days in culture. CFs migrating onto the culture plastic support or cultured on glass expressed αSMA within 3 days. The cells on the slice remained αSMA(−) despite transforming growth factor-β (20 ng/ml) or angiotensin II (200 µM) stimulation. When diastolic load was applied to myocardial slices using A-shaped stretchers, CF proliferation was significantly prevented at Days 3 and 7 (P < 0.001).ConclusionsMyocardial slices allow the study of CFs in a multicellular environment and may be used to effectively study mechanisms of cardiac fibrosis and potential targets.

  • Journal article
    Masoud S, Lim PB, Kitas GD, Panoulas Vet al., 2017,

    Sudden cardiac death in patients with rheumatoid arthritis

    , WORLD JOURNAL OF CARDIOLOGY, Vol: 9, Pages: 562-573, ISSN: 1949-8462
  • Journal article
    Yang C, Xu Y, Yu M, Lee D, Alharti S, Hellen N, Shaik NA, Banaganapalli B, Mohamoud HSA, Elango R, Przyborski S, Tenin G, Williams S, O'Sullivan J, Al-Radi OO, Atta J, Harding SE, Keavney B, Lako M, Armstrong Let al., 2017,

    Induced pluripotent stem cell modelling of HLHS underlines the contribution of dysfunctional NOTCH signalling to impaired cardiogenesis.

    , Human Molecular Genetics, Vol: 26, Pages: 3031-3045, ISSN: 0964-6906

    Hypoplastic left heart syndrome (HLHS) is among the most severe forms of congenital heart disease. Although the consensus view is that reduced flow through the left heart during development is a key factor in the development of the condition, the molecular mechanisms leading to hypoplasia of left heart structures are unknown. We have generated induced pluripotent stem cells (iPSC) from five HLHS patients and two unaffected controls, differentiated these to cardiomyocytes and identified reproducible in vitro cellular and functional correlates of the HLHS phenotype. Our data indicate that HLHS-iPSC have a reduced ability to give rise to mesodermal, cardiac progenitors and mature cardiomyocytes and an enhanced ability to differentiate to smooth muscle cells. HLHS-iPSC-derived cardiomyocytes are characterised by a lower beating rate, disorganised sarcomeres and sarcoplasmic reticulum and a blunted response to isoprenaline. Whole exome sequencing of HLHS fibroblasts identified deleterious variants in NOTCH receptors and other genes involved in the NOTCH signalling pathway. Our data indicate that the expression of NOTCH receptors was significantly downregulated in HLHS-iPSC-derived cardiomyocytes alongside NOTCH target genes confirming downregulation of NOTCH signalling activity. Activation of NOTCH signalling via addition of Jagged peptide ligand during the differentiation of HLHS-iPSC restored their cardiomyocyte differentiation capacity and beating rate and suppressed the smooth muscle cell formation. Together, our data provide firm evidence for involvement of NOTCH signalling in HLHS pathogenesis, reveal novel genetic insights important for HLHS pathology and shed new insights into the role of this pathway during human cardiac development.

  • Conference paper
    Mirza K, Zuliani C, Hou B, Ng FS, Peters N, Toumazou Cet al., 2017,

    An Individually Addressable Microneedle Device for Real-Time Wireless pH Monitoring

    , 39th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC'17)

    This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold pat- terning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.

  • Conference paper
    Mirza K, Zuliani C, Hou B, Ng FS, Peters NS, Toumazou Cet al., 2017,

    An Individually Addressable Microneedle Device for Real-Time Wireless pH Monitoring

    , 9th Annual International Conference of the IEEE Engineering in Medicine & Biology Society (EMBC'17)

    This paper describes the development of an array of individually addressable pH sensitive microneedles using injection moulding and their integration within a portable device for real-time wireless recording of pH distributions in biological samples. The fabricated microneedles are subjected to gold pat- terning followed by electrodeposition of iridium oxide to sensitize them to 0.07 units of pH change. Miniaturised electronics suitable for the sensors readout, analog-to-digital conversion and wireless transmission of the potentiometric data are embodied within the device, enabling it to measure real-time pH of soft biological samples such as muscles. In this paper, real-time recording of the cardiac pH distribution, during ischemia followed by reperfusion cycles in cardiac muscles of male Wistar rats has been demonstrated by using the microneedle array.

  • Journal article
    Jones DG, Markides V, Chow AW, Schilling RJ, Kanagaratnam P, Wong T, Davies DW, Peters NSet al., 2017,

    Characterization and consistency of interactions of triggers and substrate at the onset of paroxysmal atrial fibrillation.

    , Europace, Vol: 19, Pages: 1454-1462, ISSN: 1099-5129

    Aims: Initiating mechanisms of atrial fibrillation (AF) remain poorly understood, involving complex interaction between triggers and the atrial substrate. This study sought to classify the transitional phenomena, hypothesizing that there is consistency within and between patients in trigger-substrate interaction during transition to AF. Methods and results: Non-contact left atrial (LA) mapping was performed in 17 patients undergoing ablation for paroxysmal AF. All had spontaneous ectopy. Left atrial activation from the first ectopic to established AF was examined offline to characterize the initiating and transitional sequence of activation. In 57 fully mapped spontaneous AF initiations in 8 patients, all involved interaction of pulmonary venous/LA triggers with a septopulmonary line of block (SP-LOB) also evident in sinus rhythm, by 4 different transitional mechanisms characterized by (i) continuous focal firing: AF resulted from fragmentation of each ectopic wavefront through gaps in the SP-LOB and persisted only while focal firing continued (n = 18/32%) (ii) transient focal firing, wavefront fragmentation at the SP-LOB produced wavelet re-entry that persisted after cessation of an initiating ectopic source (n = 12/21%), (iii) of two separate interacting ectopic foci (n = 15/26%), or from (iv) transiently stable macroreentry (n = 12/21%), around the SP-LOB extending to the LA roof, resulting in progressive wavefront fragmentation. It was found that 79 ± 22% of each of the initiations in individual patients showed the same triggering mechanism. Conclusion: Onset of paroxysmal AF can be described by discrete mechanistic categories, all involving interaction of ectopic activity with a common SP-LOB. Within/between-patient consistency of initiations suggests constancy of the interacting triggers and substrate, and supports the concept of mechanistically tailored treatment.

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