Imperial College London

DrCatherineMansfield

Faculty of MedicineNational Heart & Lung Institute

Research Associate
 
 
 
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Contact

 

+44 (0)20 7594 2738catherine.mansfield07

 
 
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Location

 

ICTEM buildingHammersmith Campus

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Summary

 

Publications

Publication Type
Year
to

16 results found

Handa B, Lawal S, Wright IJ, Li X, Cabello Garcia J, Mansfield C, Chowdhury R, Peters N, Ng FSet 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.

Journal article

Kapnisi M, Mansfield C, Marijon C, Guex AG, Perbellini F, Bardi I, Humphrey EJ, Puetzer J, Mawad D, Koutsogeorgis DC, Stuckey DJ, Terracciano CM, Harding SE, Stevens MMet al., 2018, Auxetic cardiac patches with tunable mechanical and conductive properties toward treating myocardial infarction, Advanced Functional Materials, Vol: 28, ISSN: 1616-301X

An auxetic conductive cardiac patch (AuxCP) for the treatment of myocardial infarction (MI) is introduced. The auxetic design gives the patch a negative Poisson's ratio, providing it with the ability to conform to the demanding mechanics of the heart. The conductivity allows the patch to interface with electroresponsive tissues such as the heart. Excimer laser microablation is used to micropattern a re‐entrant honeycomb (bow‐tie) design into a chitosan‐polyaniline composite. It is shown that the bow‐tie design can produce patches with a wide range in mechanical strength and anisotropy, which can be tuned to match native heart tissue. Further, the auxetic patches are conductive and cytocompatible with murine neonatal cardiomyocytes in vitro. Ex vivo studies demonstrate that the auxetic patches have no detrimental effect on the electrophysiology of both healthy and MI rat hearts and conform better to native heart movements than unpatterned patches of the same material. Finally, the AuxCP applied in a rat MI model results in no detrimental effect on cardiac function and negligible fibrotic response after two weeks in vivo. This approach represents a versatile and robust platform for cardiac biomaterial design and could therefore lead to a promising treatment for MI.

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.

Journal article

Schobesberger S, Wright P, Tokar S, Bhargava A, Mansfield C, Glukhov AV, Poulet C, Buzuk A, Monszpart A, Sikkel M, Harding SE, Nikolaev VO, Lyon AR, Gorelik Jet al., 2017, T-tubule remodelling disturbs localised β2-adrenergic signalling in rat ventricular myocyte during the progression of heart failure, Cardiovascular Research, Vol: 113, Pages: 770-782, ISSN: 0008-6363

AimsCardiomyocyte β2-adrenergic receptor (β2AR) cyclic adenosine monophosphate (cAMP) signalling is regulated by the receptors’ subcellular location within transverse tubules (T-tubules), via interaction with structural and regulatory proteins, which form a signalosome. In chronic heart failure (HF), β2ARs redistribute from T-tubules to the cell surface, which disrupts functional signalosomes and leads to diffuse cAMP signalling. However, the functional consequences of structural changes upon β2AR-cAMP signalling during progression from hypertrophy to advanced HF are unknown.Methods and resultsRat left ventricular myocytes were isolated at 4-, 8-, and 16-week post-myocardial infarction (MI), β2ARs were stimulated either via whole-cell perfusion or locally through the nanopipette of the scanning ion conductance microscope. cAMP release was measured via a Förster Resonance Energy Transfer-based sensor Epac2-camps. Confocal imaging of di-8-ANNEPS-stained cells and immunoblotting were used to determine structural alterations. At 4-week post-MI, T-tubule regularity, density and junctophilin-2 (JPH2) expression were significantly decreased. The amplitude of local β2AR-mediated cAMP in T-tubules was reduced and cAMP diffused throughout the cytosol instead of being locally confined. This was accompanied by partial caveolin-3 (Cav-3) dissociation from the membrane. At 8-week post-MI, the β2AR-mediated cAMP response was observed at the T-tubules and the sarcolemma (crest). Finally, at 16-week post-MI, the whole cell β2AR-mediated cAMP signal was depressed due to adenylate cyclase dysfunction, while overall Cav-3 levels were significantly increased and a substantial portion of Cav-3 dissociated into the cytosol. Overexpression of JPH2 in failing cells in vitro or AAV9.SERCA2a gene therapy in vivo did not improve β2AR-mediated signal compartmentation or reduce cAMP diffusion.ConclusionAlthough changes in T-tubule structure

Journal article

Mawad D, Mansfield C, Lauto A, Perbellini F, Nelson G, Tonkin J, Bello S, Carrod D, Micolich A, Mahat M, Simonotto J, Payne D, Lyon A, Gooding J, Harding S, Terracciano C, Stevens MMet al., 2016, A conducting polymer with enhanced electronic stability applied in cardiac models, Science Advances, Vol: 2, ISSN: 2375-2548

Electrically active constructs can have a beneficial effect on electroresponsive tissues, such as the brain, heart, and nervous system. Conducting polymers (CPs) are being considered as components of these constructs because of their intrinsic electroactive and flexible nature. However, their clinical application has been largely hampered by their short operational time due to a decrease in their electronic properties. We show that, by immobilizing the dopant in the conductive scaffold, we can prevent its electric deterioration. We grew polyaniline (PANI) doped with phytic acid on the surface of a chitosan film. The strong chelation between phytic acid and chitosan led to a conductive patch with retained electroactivity, low surface resistivity (35.85 ± 9.40 kilohms per square), and oxidized form after 2 weeks of incubation in physiological medium. Ex vivo experiments revealed that the conductive nature of the patch has an immediate effect on the electrophysiology of the heart. Preliminary in vivo experiments showed that the conductive patch does not induce proarrhythmogenic activities in the heart. Our findings set the foundation for the design of electronically stable CP-based scaffolds. This provides a robust conductive system that could be used at the interface with electroresponsive tissue to better understand the interaction and effect of these materials on the electrophysiology of these tissues.

Journal article

Sanchez-Alonso JL, Bhargava A, O'Hara T, Glukhov AV, Schobesberger S, Bhogal NK, Sikkel MB, Mansfield C, Korchev YE, Lyon AR, Punjabi PP, Nikolaev VO, Trayanova NA, Gorelik Jet al., 2016, Microdomain-Specific Modulation of L-type Calcium Channels Leads to Triggered Ventricular Arrhythmia in Heart Failure, Circulation Research, Vol: 119, Pages: 944-955, ISSN: 1524-4571

RATIONALE: Disruption in subcellular targeting of Ca(2+) signaling complexes secondary to changes in cardiac myocyte structure may contribute to the pathophysiology of a variety of cardiac diseases, including heart failure (HF) and certain arrhythmias. OBJECTIVE: To explore microdomain-targeted remodeling of ventricular L-type Ca(2+) channels (LTCCs) in HF. METHODS AND RESULTS: Super-resolution scanning patch-clamp, confocal and fluorescence microscopy were used to explore distribution of single LTCCs in different membrane microdomains of non-failing and failing human and rat ventricular myocytes. Disruption of membrane structure in both species led to re-distribution of functional LTCCs from their canonical location in transversal tubules (T-tubules) to the non-native crest of the sarcolemma, where their open probability (Po) was dramatically increased (0.034±0.011 vs 0.154±0.027, P<0.001). High Po was linked to enhanced calcium-calmodulin kinase II (CaMKII)-mediated phosphorylation in non-native microdomains and resulted in an elevated ICa,L window current which contributed to the development of early afterdepolarizations (EADs). A novel model of LTCC function in HF was developed; following its validation with experimental data, the model was used to ascertain how HF-induced T-tubule loss led to altered LTCC function and EADs. The HF myocyte model was then implemented in a 3D left ventricle model, demonstrating that such EADs can propagate and initiate reentrant arrhythmias. CONCLUSIONS: Microdomain-targeted remodeling of LTCC properties is an important event in pathways that may contribute to ventricular arrhythmogenesis in the settings of HF-associated remodeling. This extends beyond the classical concept of electrical remodelling in HF and adds a new dimension to cardiovascular disease.

Journal article

Buyandelger B, Mansfield C, Luther P, Knoell Ret al., 2016, ZBTB17 is a novel cardiomyopathy candidate gene and regulates autophagy in the heart, Cardiovascular Research, Vol: 111, Pages: S36-S36, ISSN: 1755-3245

Journal article

Mansfield C, Mawad D, Perbellini F, Tonkin J, Bello SO, Simonotto JD, Lyon AR, Stevens MM, Terracciano CM, Harding SEet al., 2016, A novel conductive patch for application in cardiac tissue engineering, Cardiovascular Research, Vol: 111, Pages: S41-S41, ISSN: 1755-3245

Journal article

Buyandelger B, Mansfield C, Kostin S, Choi O, Roberts AM, Ware JS, Mazzarotto F, Pesce F, Buchan R, Isaacson RL, Vouffo J, Gunkel S, Knöll G, McSweeney SJ, Wei H, Perrot A, Pfeiffer C, Toliat MR, Ilieva K, Krysztofinska E, López-Olañeta MM, Gómez-Salinero JM, Schmidt A, Ng KE, Teucher N, Chen J, Teichmann M, Eilers M, Haverkamp W, Regitz-Zagrosek V, Hasenfuss G, Braun T, Pennell DJ, Gould I, Barton PJ, Lara-Pezzi E, Schafer S, Hübner N, Felkin LE, O'Regan DP, Petretto E, Brand T, Milting H, Nürnberg P, Schneider MD, Prasad S, Knöll Ret al., 2015, ZBTB17 (MIZ1) Is Important for the Cardiac Stress Response and a Novel Candidate Gene for Cardiomyopathy and Heart Failure., Circulation. Cardiovascular Genetics, Vol: 8, Pages: 643-652, ISSN: 1942-3268

BACKGROUND: -Mutations in sarcomeric and cytoskeletal proteins are a major cause of hereditary cardiomyopathies, but our knowledge remains incomplete as to how the genetic defects execute their effects. METHODS AND RESULTS: -We used cysteine and glycine-rich protein 3 (CSRP3), a known cardiomyopathy gene, in a yeast two-hybrid screen and identified zinc finger and BTB domain containing protein 17 (ZBTB17) as a novel interacting partner. ZBTB17 is a transcription factor that contains the peak association signal (rs10927875) at the replicated 1p36 cardiomyopathy locus. ZBTB17 expression protected cardiac myocytes from apoptosis in vitro and in a mouse model with cardiac myocyte-specific deletion of Zbtb17, which develops cardiomyopathy and fibrosis after biomechanical stress. ZBTB17 also regulated cardiac myocyte hypertrophy in vitro and in vivo in a calcineurin-dependent manner. CONCLUSIONS: -We revealed new functions for ZBTB17 in the heart, a transcription factor which may play a role as a novel cardiomyopathy gene.

Journal article

Buyandelger B, Mansfield C, Knoell R, 2014, Mechano-signaling in heart failure (vol 466, pg 1093, 2014), PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 466, Pages: 1845-1845, ISSN: 0031-6768

Journal article

Mansfield C, Buyandelger B, Kostin S, Knoell G, Toliat MR, Perrot A, Haverkamp W, Milting H, Nurnberg P, Knoell Ret al., 2014, The role of MIP1 in cardiac myocyte hypertrophy and survival, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363

Journal article

Buyandelger B, Mansfield C, Kostin S, Choi O, Isaacson RL, Knoell G, Mcsweeney SJ, Lara-Pezzi E, Milting H, Knoell Ret al., 2014, MIP1 causes cardiomyopathy, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363

Journal article

Buyandelger B, Mansfield C, Knoell R, 2014, Mechano-signaling in heart failure, PFLUGERS ARCHIV-EUROPEAN JOURNAL OF PHYSIOLOGY, Vol: 466, Pages: 1093-1099, ISSN: 0031-6768

Journal article

Paur H, Wright PT, Sikkel MB, Tranter MH, Mansfield C, O'Gara P, Stuckey DJ, Nikolaev VO, Diakonov I, Pannell L, Gong H, Sun H, Peters NS, Petrou M, Zheng Z, Gorelik J, Lyon AR, Harding SEet al., 2012, High levels of circulating epinephrine trigger apical cardiodepression in a β2-adrenergic receptor/Gi-dependent manner: a new model of Takotsubo cardiomyopathy., Circulation Journal, Vol: 6, Pages: 697-706

Journal article

Mansfield C, West TG, Curtin NA, Ferenczi MAet al., 2012, Stretch of Contracting Cardiac Muscle Abruptly Decreases the Rate of Phosphate Release at High and Low Calcium, JOURNAL OF BIOLOGICAL CHEMISTRY, Vol: 287, Pages: 25696-25705

Journal article

Song W, Dyer E, Stuckey D, Leung M-C, Memo M, Mansfield C, Ferenczi M, Liu K, Redwood C, Nowak K, Harding S, Clarke K, Wells D, Marston Set al., 2010, Investigation of a transgenic mouse model of familial dilated cardiomyopathy, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 49, Pages: 380-389, ISSN: 0022-2828

Journal article

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