Imperial College London

ProfessorSianHarding

Faculty of MedicineNational Heart & Lung Institute

Emeritus Professor of Cardiac Pharmacology
 
 
 
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Contact

 

+44 (0)20 7594 3009sian.harding Website

 
 
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Location

 

435ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

435 results found

Tranter MH, Redfors B, Wright PT, Couch LS, Lyon AR, Omerovic E, Harding SEet al., 2022, Hyperthermia as a trigger for Takotsubo syndrome in a rat model, Frontiers in Cardiovascular Medicine, Vol: 9, Pages: 1-9

Takotsubo syndrome is a well-characterized cause of acute yet reversible heart failure associated with periods of intense emotional stress, often mimicking on presentation an acute coronary syndrome. Animal models of Takotsubo syndrome have been developed, either through the application of a stressor, or administration of exogenous catecholamine. We found that in a model of isoproterenol-induced Takotsubo syndrome in anesthetized rats hyperthermia (40–41°C) would occur after the administration of isoproterenol. Maintenance of this hyperthermia would result in an apical hypocontractility typical of the syndrome, whereas prevention of hyperthermia with active cooling to maintain a euthermic core body temperature prevented (but did not subsequently reverse) apical hypocontractility. In vitro experimentation with isolated cardiomyocytes showed no effect of hyperthermia on either baseline contractility or contractility change after beta-adrenoceptor stimulation. We suggest that the rise in body temperature that is characteristic of catecholamine storm may be a component in the development of Takotsubo syndrome.

Journal article

Couch LS, Fiedler J, Chick G, Clayton R, Dries E, Wienecke LM, Fu L, Fourre J, Pandey P, Derda AA, Wang BX, Jabbour R, Shanmuganathan M, Wright P, Lyon AR, Terracciano CM, Thum T, Harding SEet al., 2022, Circulating microRNAs predispose to takotsubo syndrome following high-dose adrenaline exposure, Cardiovascular Research, Vol: 118, Pages: 1758-1770, ISSN: 0008-6363

AIMS: Takotsubo syndrome (TTS) is an acute heart failure, typically triggered by high adrenaline during physical or emotional stress. It is distinguished from myocardial infarction (MI) by a characteristic pattern of ventricular basal hypercontractility with hypokinesis of apical segments, and absence of coronary occlusion. We aimed to understand whether recently discovered circulating biomarkers miR-16 and miR-26a, which differentiate TTS from MI at presentation, were mechanistically involved in the pathophysiology of TTS. METHODS AND RESULTS: miR-16 and miR-26a were co-overexpressed in rats with AAV and TTS induced with an adrenaline bolus. Untreated isolated rat cardiomyocytes were transfected with pre-/anti-miRs and functionally assessed. Ventricular basal hypercontraction and apical depression were accentuated in miR-transfected animals after induction of TTS. In vitro miR-16 and/or miR-26a overexpression in isolated apical (but not basal) cardiomyocytes produced strong depression of contraction, with loss of adrenaline sensitivity. They also enhanced the initial positive inotropic effect of adrenaline in basal cells. Decreased contractility after TTS-miRs was reproduced in non-failing human apical cardiomyocytes. Bioinformatic profiling of miR targets, followed by expression assays and functional experiments, identified reductions of CACNB1 (L-type calcium channel Cavβ subunit), RGS4 (regulator of G-protein signalling 4) and G-protein subunit Gβ (GNB1) as underlying these effects. CONCLUSION: miR-16 and miR-26a sensitise the heart to TTS-like changes produced by adrenaline. Since these miRs have been associated with anxiety and depression, they could provide a mechanism whereby priming of the heart by previous stress causes an increased likelihood of TTS in the future. TRANSLATIONAL PERSPECTIVE: TTS-associated miRs have the potential to be active players predisposing to TTS. Feasibly, their measurement in recovered TTS patients during subsequent peri

Journal article

Fassina D, Costa CM, Longobardi S, Karabelas E, Plank G, Harding SE, Niederer SAet al., 2022, Modelling the interaction between stem cells derived cardiomyocytes patches and host myocardium to aid non-arrhythmic engineered heart tissue design, PLOS COMPUTATIONAL BIOLOGY, Vol: 18, ISSN: 1553-734X

Journal article

Roy I, Dubey P, Majid Q, Fricker A, Gregory D, Grigsby C, Stevens MM, Terracciano C, Harding SEet al., 2022, POLYHYDROXYALKANOATES, NATURAL MATERIALS OF BACTERIAL ORIGIN, IDEAL FOR CARDIAC TISSUE ENGINEERING, Publisher: MARY ANN LIEBERT, INC, Pages: S36-S37, ISSN: 1937-3341

Conference paper

Pitoulis FG, Nunez-Toldra R, Xiao K, Kit-Anan W, Mitzka S, Jabbour RJ, Harding SE, Perbellini F, Thum T, de Tombe PP, Terracciano CMet al., 2022, Remodelling of adult cardiac tissue subjected to physiological and pathological mechanical load in vitro, Cardiovascular Research, Vol: 118, Pages: 814-827, ISSN: 0008-6363

Aims:Cardiac remodelling is the process by which the heart adapts to its environment. Mechanical load is a major driver of remodelling. Cardiac tissue culture has been frequently employed for in vitro studies of load-induced remodelling; however, current in vitro protocols (e.g. cyclic stretch, isometric load, and auxotonic load) are oversimplified and do not accurately capture the dynamic sequence of mechanical conformational changes experienced by the heart in vivo. This limits translational scope and relevance of findings.Methods and results:We developed a novel methodology to study chronic load in vitro. We first developed a bioreactor that can recreate the electromechanical events of in vivo pressure–volume loops as in vitro force–length loops. We then used the bioreactor to culture rat living myocardial slices (LMS) for 3 days. The bioreactor operated based on a 3-Element Windkessel circulatory model enabling tissue mechanical loading based on physiologically relevant parameters of afterload and preload. LMS were continuously stretched/relaxed during culture simulating conditions of physiological load (normal preload and afterload), pressure-overload (normal preload and high afterload), or volume-overload (high preload & normal afterload). At the end of culture, functional, structural, and molecular assays were performed to determine load-induced remodelling. Both pressure- and volume-overloaded LMS showed significantly decreased contractility that was more pronounced in the latter compared with physiological load (P < 0.0001). Overloaded groups also showed cardiomyocyte hypertrophy; RNAseq identified shared and unique genes expressed in each overload group. The PI3K-Akt pathway was dysregulated in volume-overload while inflammatory pathways were mostly associated with remodelling in pressure-overloaded LMS.Conclusion:We have developed a proof-of-concept platform and methodology to recreate remodelling under pathophysiol

Journal article

Boyalla V, Harling L, Snell A, Kralj-Hans I, Barradas-Pires A, Haldar S, Khan HR, Cleland JGF, Athanasiou T, Harding SE, Wong Tet al., 2022, Biomarkers as predictors of recurrence of atrial fibrillation post ablation: an updated and expanded systematic review and meta-analysis, CLINICAL RESEARCH IN CARDIOLOGY, Vol: 111, Pages: 680-691, ISSN: 1861-0684

Journal article

Gara E, Zucchelli E, Nemes A, Jakus Z, Ajtay K, Kemecsei E, Kiszler G, Hegedus N, Szigeti K, Foldes I, Arvai K, Kosa J, Kolev K, Komorowicz E, Padmanabhan P, Maurovich-Horvat P, Dosa E, Varady G, Polos M, Hartyanszky I, Harding SE, Merkely B, Mathe D, Szabo G, Radovits T, Foldes Get al., 2022, 3D culturing of human pluripotent stem cells-derived endothelial cells for vascular regeneration, THERANOSTICS, Vol: 12, Pages: 4684-4702, ISSN: 1838-7640

Journal article

Tranter MH, Redfors B, Wright PT, Couch LS, Lyon AR, Omerovic E, Harding SEet al., 2022, Corrigendum: Hyperthermia as a trigger for Takotsubo syndrome in a rat model., Front Cardiovasc Med, Vol: 9, ISSN: 2297-055X

[This corrects the article DOI: 10.3389/fcvm.2022.869585.].

Journal article

Berecz T, Yiu A, Vittay O, Orsolits B, Mioulane M, dos Remedios CG, Ketteler R, Merkely B, Apati A, Harding SE, Hellen N, Foldes Get al., 2021, Transcriptional co-activators YAP1-TAZ of Hippo signalling in doxorubicin-induced cardiomyopathy, ESC HEART FAILURE, Vol: 9, Pages: 224-235, ISSN: 2055-5822

Journal article

Ontoria-Oviedo I, Foeldes G, Tejedor S, Panadero J, Kitani T, Vazquez A, Wu JC, Harding SE, Sepulveda Pet al., 2021, Modeling Transposition of the Great Arteries with Patient-Specific Induced Pluripotent Stem Cells, INTERNATIONAL JOURNAL OF MOLECULAR SCIENCES, Vol: 22

Journal article

Wright PT, Gorelik J, Harding SE, 2021, Electrophysiological remodeling: cardiac t-tubules and β-adrenoceptors, Cells, Vol: 10, ISSN: 2073-4409

Beta-adrenoceptors (βAR) are often viewed as archetypal G-protein coupled receptors. Over the past fifteen years, investigations in cardiovascular biology have provided remarkable insights into this receptor family. These studies have shifted pharmacological dogma, from one which centralized the receptor to a new focus on structural micro-domains such as caveolae and t-tubules. Important studies have examined, separately, the structural compartmentation of ion channels and βAR. Despite links being assumed, relatively few studies have specifically examined the direct link between structural remodeling and electrical remodeling with a focus on βAR. In this review, we will examine the nature of receptor and ion channel dysfunction on a substrate of cardiomyocyte microdomain remodeling, as well as the likely ramifications for cardiac electrophysiology. We will then discuss the advances in methodologies in this area with a specific focus on super-resolution microscopy, fluorescent imaging, and new approaches involving microdomain specific, polymer-based agonists. The advent of powerful computational modelling approaches has allowed the science to shift from purely empirical work, and may allow future investigations based on prediction. Issues such as the cross-reactivity of receptors and cellular heterogeneity will also be discussed. Finally, we will speculate as to the potential developments within this field over the next ten years.

Journal article

Fu L, Zhang H, Machuki JO, Zhang T, Han L, Sang L, Wu L, Zhao Z, Turley MJ, Hu X, Hou H, Li D, Harding SE, Sun Het al., 2021, Reply to: Estrogens for protection from an index and recurrent episodes of takotsubo syndrome? REPLY, JOURNAL OF ENDOCRINOLOGY, Vol: 250, Pages: L3-L3, ISSN: 0022-0795

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

Basnett P, Matharu RK, Taylor CS, Illangakoon U, Dawson J, Kanczler JM, Behbehani M, Humphrey E, Majid Q, Lukasiewicz B, Nigmatullin R, Heseltine P, Oreffo ROC, Haycock JW, Terracciano C, Harding SE, Edirisinghe M, Roy Iet al., 2021, Harnessing Polyhydroxyalkanoates and Pressurized Gyration for Hard and Soft Tissue Engineering, ACS APPLIED MATERIALS & INTERFACES, Vol: 13, Pages: 32624-32639, ISSN: 1944-8244

Journal article

Fu L, Zhang H, Machuki JO, Zhang T, Han L, Sang L, Wu L, Zhao Z, Turley MJ, Hu X, Hou H, Li D, Harding SE, Sun Het al., 2021, GPER mediates estrogen cardioprotection against epinephrine-induced stress, JOURNAL OF ENDOCRINOLOGY, Vol: 249, Pages: 209-222, ISSN: 0022-0795

Journal article

Cuello F, Knaust AE, Saleem U, Loos M, Raabe J, Mosqueira D, Laufer S, Schweizer M, van Der Kraak P, Flenner F, Ulmer BM, Braren I, Yin X, Theofilatos K, Ruiz-Orera J, Patone G, Klampe B, Schulze T, Piasecki A, Pinto Y, Vink A, Hubner N, Harding S, Mayr M, Denning C, Eschenhagen T, Hansen Aet al., 2021, Impairment of the ER/mitochondria compartment in human cardiomyocytes with PLN p.Arg14del mutation, EMBO MOLECULAR MEDICINE, Vol: 13, ISSN: 1757-4676

Journal article

Narodden S, 2021, Shockwave for the abrogation of heart failure in myocardial ischaemia-reperfusion injury

Thesis dissertation

Dvinskikh L, Harding S, Sparks H, Gorelik J, MacLeod K, Dunsby Cet al., 2021, High speed imaging of calcium dynamics in cardiomyocytes with a flexible light-sheet fluorescence microscope, Biophotonics Congress 2021

Conference paper

Kondrashov A, Mohd Yusof NAN, Hasan A, Goulding J, Kodagoda T, Hoang DM, Vo NTN, Melarangi T, Dolatshad N, Gorelik J, Hill SJ, Harding SE, Denning Cet al., 2021, CRISPR/Cas9-mediated generation and analysis of N terminus polymorphic models of β2AR in isogenic hPSC-derived cardiomyocytes, Molecular Therapy - Methods and Clinical Development, Vol: 20, Pages: 39-53, ISSN: 2329-0501

During normal- and patho-physiological situations, the behavior of the beta2-adrenoreceptor (β2AR) is influenced by polymorphic variants. The functional impact of such polymorphisms has been suggested from data derived from genetic association studies, in vitro experiments with primary cells, and transgenic overexpression models. However, heterogeneous genetic background and non-physiological transgene expression levels confound interpretation, leading to conflicting mechanistic conclusions. To overcome these limitations, we used CRISPR/Cas9 gene editing technology in human pluripotent stem cells (hPSCs) to create a unique suite of four isogenic homozygous variants at amino acid positions 16(G/R) and 27(G/Q), which reside in the N terminus of the β2AR. By producing cardiomyocytes from these hPSC lines, we determined that at a functional level β2AR signaling dominated over β1AR . Examining changes in beat rates and responses to isoprenaline, Gi coupling, cyclic AMP (cAMP) production, downregulation, and desensitization indicated that responses were often heightened for the GE variant, implying differential dominance of both polymorphic location and amino acid substitution. This finding was corroborated, since GE showed hypersensitivity to doxorubicin-induced cardiotoxicity relative to GQ and RQ variants. Thus, understanding the effect of β2AR polymorphisms on cardiac response to anticancer therapy may provide a route for personalized medicine and facilitate immediate clinical impact.

Journal article

Kit-Anan W, Mazo M, Wang BX, Leonardo V, Pence I, Gopal S, Gelmi A, Becce M, Chiappini C, Harding SE, Terracciano C, Stevens Met al., 2021, Multiplexing physical stimulation on single human induced pluripotent stem cell-derived cardiomyocytes for phenotype modulation, Biofabrication, Vol: 13, Pages: 1-16, ISSN: 1758-5082

Traditional in vitro bioengineering approaches whereby only individual biophysical cues are manipulated at any one time are highly inefficient, falling short when recapitulating the complexity of the cardiac environment. Multiple biophysical cues are present in the native myocardial niche and are essential during development, as well as in maintenance of adult cardiomyocyte (CM) phenotype in both health and disease. This study establishes a novel biofabrication workflow to study and manipulate hiPSC-CMs and to understand how these cells respond to a multiplexed biophysical environment, namely microscopic topography (3D shape resembling that of adult CM) and substrate stiffness, at a single cell level. Silicon masters were fabricated and developed to generate pillars of the desired 3D shapes, which would be used to mould the designed microwell arrays into a hydrogel. Polyacrylamide was modified with the incorporation of acrylic acid to provide a carboxylic group conjugation site for adhesion motifs, without comprising its capacity to modulate the stiffness. In this manner, individual parameters can be finely tuned independently within the hydrogel: the dimension of 3D shaped microwell and its stiffness. The design allows the platform to isolate single hiPSC-CMs to study solely biophysical cues in an absence of cell-cell physical interaction. Under physiologic-like physical conditions (3D shape resembling that of adult CM and 9.83 kPa substrate stiffness), isolated single hiPSC-CMs exhibit increased Cx-43 density, cell Peer reviewed version of the manuscript published in final form at Biofabrication (2020). membrane stiffness and calcium transient amplitude; co-expression of the subpopulation-related MYL2- MYL7 proteins; while displaying higher anisotropism in comparison to pathologic-like conditions (flat surface and 112 kPa substrate stiffness). This demonstrates that supplying a physiological or pathological microenvironment to an isolated single hiPSC-CM in absen

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

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

Crestani T, Steichen C, Neri E, Rodrigues M, Fonseca-Alaniz MH, Ormrod B, Holt MR, Pandey P, Harding S, Ehler E, Krieger JEet al., 2020, Electrical stimulation applied during differentiation drives the hiPSC-CMs towards a mature cardiac conduction-like cells, BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, Vol: 533, Pages: 376-382, ISSN: 0006-291X

Journal article

Hasan A, Mohammadi N, Nawaz A, Kodagoda T, Diakonov I, Harding SE, Gorelik Jet al., 2020, Age-dependent maturation of iPSC-CMs leads to the enhanced compartmentation of beta(2)AR-cAMP signalling, Cells, Vol: 9, ISSN: 2073-4409

The ability to differentiate induced-pluripotent stem cells into cardiomyocytes (iPSC-CMs) has opened up novel avenues for potential cardiac therapies. However, iPSC-CMs exhibit a range of somewhat immature functional properties. This study explored the development of the beta-adrenergic receptor (βAR) pathway, which is crucial in regulating contraction and signifying the health and maturity of myocytes. We explored the compartmentation of β2AR-signalling and phosphodiesterases (PDEs) in caveolae, as functional nanodomains supporting the mature phenotype. Förster Resonance Energy Transfer (FRET) microscopy was used to study the cyclic adenosine monophosphate (cAMP) levels in iPSC-CMs at day 30, 60, and 90 following βAR subtype-specific stimulation. Subsequently, the PDE2, PDE3, and PDE4 activity was investigated using specific inhibitors. Cells were treated with methyl-β-cyclodextrin (MβCD) to remove cholesterol as a method of decompartmentalising β2AR. As iPSC-CMs mature with a prolonged culture time, the caveolae density is increased, leading to a reduction in the overall cytoplasmic cAMP signal stimulated through β2AR (but not β1AR). Pan-phosphodiesterase inhibition or caveolae depletion leads to an increase in the β2AR-stimulated cytoplasmic cAMP. Moreover, with time in culture, the increase in the βAR-dependent cytoplasmic cAMP becomes more sensitive to cholesterol removal. The regulation of the β2AR response by PDE2 and 4 is similarly increased with the time in culture. We conclude that both the β2AR and PDEs are restricted to the caveolae nanodomains, and thereby exhibit a tighter spatial restriction over the cAMP signal in late-stage compared to early iPSC-CMs.

Journal article

Meijles DN, Cull JJ, Markou T, Cooper STE, Haines ZHR, Fuller SJ, O'Gara P, Sheppard MN, Harding SE, Sugden PH, Clerk Aet al., 2020, Redox Regulation of Cardiac ASK1 (Apoptosis Signal-Regulating Kinase 1) Controls p38-MAPK (Mitogen-Activated Protein Kinase) and Orchestrates Cardiac Remodeling to Hypertension, HYPERTENSION, Vol: 76, Pages: 1208-1218, ISSN: 0194-911X

Journal article

Majid QA, Fricker ATR, Gregory DA, Davidenko N, Hernandez Cruz O, Jabbour RJ, Owen TJ, Basnett P, Lukasiewicz B, Stevens M, Best S, Cameron R, Sinha S, Harding SE, Roy Iet al., 2020, Natural biomaterials for cardiac tissue engineering: a highly biocompatible solution., Frontiers in Cardiovascular Medicine, Vol: 7, Pages: 1-32, ISSN: 2297-055X

Cardiovascular diseases (CVD) constitute a major fraction of the current major global diseases and lead to about 30% of the deaths, i.e., 17.9 million deaths per year. CVD include coronary artery disease (CAD), myocardial infarction (MI), arrhythmias, heart failure, heart valve diseases, congenital heart disease, and cardiomyopathy. Cardiac Tissue Engineering (CTE) aims to address these conditions, the overall goal being the efficient regeneration of diseased cardiac tissue using an ideal combination of biomaterials and cells. Various cells have thus far been utilized in pre-clinical studies for CTE. These include adult stem cell populations (mesenchymal stem cells) and pluripotent stem cells (including autologous human induced pluripotent stem cells or allogenic human embryonic stem cells) with the latter undergoing differentiation to form functional cardiac cells. The ideal biomaterial for cardiac tissue engineering needs to have suitable material properties with the ability to support efficient attachment, growth, and differentiation of the cardiac cells, leading to the formation of functional cardiac tissue. In this review, we have focused on the use of biomaterials of natural origin for CTE. Natural biomaterials are generally known to be highly biocompatible and in addition are sustainable in nature. We have focused on those that have been widely explored in CTE and describe the original work and the current state of art. These include fibrinogen (in the context of Engineered Heart Tissue, EHT), collagen, alginate, silk, and Polyhydroxyalkanoates (PHAs). Amongst these, fibrinogen, collagen, alginate, and silk are isolated from natural sources whereas PHAs are produced via bacterial fermentation. Overall, these biomaterials have proven to be highly promising, displaying robust biocompatibility and, when combined with cells, an ability to enhance post-MI cardiac function in pre-clinical models. As such, CTE has great potential for future clinical solutions and he

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

Forte E, Alsubaie M, Perkins B, Sintou A, Chowdhury R, Harding SE, Furtado M, Hasham MG, Rosenthal N, Sattler SSet al., 2020, Post-MI dendritic cells trigger an adaptive immune reaction, and cytotoxic T cells persist during heart failure., Publisher: WILEY, Pages: 265-265, ISSN: 1388-9842

Conference paper

Sintou A, Mansfield C, Iacob A-O, Chowdhury RA, Narodden S, Rothery SM, Podoveo R, Sanchez Alonso JL, Ferraro E, Swiatlowska P, Harding S, Prasad S, Rosenthal N, Gorelik J, Sattler Set al., 2020, Mediastinal lymphadenopathy, class-switched auto-antibodies and myocardial immune-complexes during heart failure in rodents and humans, Frontiers in Cell and Developmental Biology, Vol: 8, Pages: 1-12, ISSN: 2296-634X

Mediastinal lymphadenopathy and auto-antibodies are clinical phenomena during ischemicheart failure pointing to an autoimmune response against the heart. T and B cell have beenconvincingly demonstrated to be activated after myocardial infarction, a prerequisite for thegeneration of mature auto-antibodies. Yet, little is known about the immunoglobulin isotyperepertoire thus pathological potential of anti-heart auto-antibodies during heart failure.We obtained human myocardial tissue from ischemic heart failure patients and inducedexperimental MI in rats. We found that anti-heart autoimmunity persists during heart failure.Rat mediastinal lymph nodes are enlarged and contain active secondary follicles with matureisotype-switched IgG2a B cells. Mature IgG2a auto-antibodies specific for cardiac antigens arepresent in rat heart failure serum, and IgG and complement C3 deposits are evident in heartfailure tissue of both rats and human patients.Previously established myocardial inflammation, and the herein provided proof of B cellmaturation in lymph nodes and myocardial deposition of mature auto-antibodies, provide allthe hallmark signs of an established autoimmune response in chronic heart failure.

Journal article

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