23 results found
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
Ferraro E, Pozhidaeva L, Pitcher DS, et al., 2020, Prolonged ursodeoxycholic acid administration reduces acute ischaemia-induced arrhythmias in adult rat hearts, Scientific Reports, Vol: 10, Pages: 1-13, ISSN: 2045-2322
Acute myocardial ischaemiaand reperfusion (I-R) are major causes of ventricular arrhythmias in patients with a history of coronary artery disease. Ursodeoxycholic acid (UDCA)has previously been shown to be antiarrhythmic in fetal hearts.This study was performed to investigate if UDCA protects against ischaemia-induced and reperfusion-induced arrhythmias in the adult myocardium,43andcomparesthe effect of acute (perfusion only) versus prolonged (2 weeks pre-treatment plus perfusion) UDCA administration. Langendorff-perfused adult Sprague-Dawley rat hearts were subjected to acute regional ischaemia by ligation of the left anterior descending artery(10 minutes), followed by reperfusion (2 minutes), and arrhythmia incidence quantified. Prolonged UDCA administration reduced the incidence of acute ischaemia-induced arrhythmias (p=0.028),with a eduction in number of ventricular ectopic beats during the ischaemic phase compared with acute treatment(10±3 vs 58±15, p=0.036).No antiarrhythmic effect was observed in the acute UDCA administration group. Neither acute nor prolonged UDCA treatment altered the incidence of reperfusion arrhythmias.The antiarrhythmic effect of UDCA maybe partially mediated by an increase in cardiac wavelength, due tothe attenuation of conduction velocity slowing (p=0.03), and the preservation of Connexin43 phosphorylation during acute ischaemia(p=0.0027). The potential antiarrhythmic effects of prolonged UDCA administration merit further investigation.
Sintou A, Mansfield C, Iacob A-O, et 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.
Swiatlowska P, Sanchez-Alonso JL, Mansfield C, et al., 2020, Short-term angiotensin II treatment regulates cardiac nanomechanics via microtubule modifications., Nanoscale, Vol: 12, Pages: 16315-16329, ISSN: 2040-3364
Mechanical properties of single myocytes contribute to the whole heart performance, but the measurement of mechanics in living cells at high resolution with minimal force interaction remains challenging. Angiotensin II (AngII) is a peptide hormone that regulates a number of physiological functions, including heart performance. It has also been shown to contribute to cell mechanics by inducing cell stiffening. Using non-contact high-resolution Scanning Ion Conductance Microscopy (SICM), we determine simultaneously cell topography and membrane transverse Young's modulus (YM) by a constant pressure application through a nanopipette. While applying pressure, the vertical position is recorded and a deformation map is generated from which YM can be calculated and corrected for the uneven geometry. High resolution of this method also allows studying specific membrane subdomains, such as Z-grooves and crests. We found that short-term AngII treatment reduces the transversal YM in isolated adult rat cardiomyocytes acting via an AT1 receptor. Blocking either a TGF-β1 receptor or Rho kinase abolishes this effect. Analysis of the cytoskeleton showed that AngII depletes microtubules by decreasing long-lived detyrosinated and acetylated microtubule populations. Interestingly, in the failing cardiomyocytes, which are stiffer than controls, the short-term AngII treatment also reduces the YM, thus normalizing the mechanical state of cells. This suggests that the short-term softening effect of AngII on cardiac cells is opposite to the well-characterized long-term hypertrophic effect. In conclusion, we generate a precise nanoscale indication map of location-specific transverse cortical YM within the cell and this can substantially advance our understanding of cellular mechanics in a physiological environment, for example in isolated cardiac myocytes.
Rifai SE, Sintou A, Mansfield C, et al., 2020, Humoral factors in serum of rats with chronic heart failure induce cardiomyocyte hypertrophy and reduce viability., Clinical medicine (London, England), Vol: 20, Pages: s107-s107, ISSN: 1470-2118
Schobesberger S, Wright PT, Poulet C, et al., 2020, beta(3)-Adrenoceptor redistribution impairs NO/cGMP/PDE2 signalling in failing cardiomyocytes, eLife, Vol: 9, Pages: 1-15, ISSN: 2050-084X
Cardiomyocyte β3-adrenoceptors (β3-ARs) coupled to soluble guanylyl cyclase (sGC)-dependent production of the second messenger 3’,5’-cyclic guanosine monophosphate (cGMP) have been shown to protect from heart failure. However, the exact localization of these receptors to fine membrane structures and subcellular compartmentation of β3-AR/cGMP signals underpinning this protection in health and disease remain elusive. Here, we used a Förster Resonance Energy Transfer (FRET)-based cGMP biosensor combined with scanning ion conductance microscopy (SICM) to show that functional β3-ARs are mostly confined to the T-tubules of healthy rat cardiomyocytes. Heart failure, induced via myocardial infarction, causes a decrease of the cGMP levels generated by these receptors and a change of subcellular cGMP compartmentation. Furthermore, attenuated cGMP signals led to impaired phosphodiesterase two dependent negative cGMP-to-cAMP cross-talk. In conclusion, topographic and functional reorganization of the β3-AR/cGMP signalosome happens in heart failure and should be considered when designing new therapies acting via this receptor.
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.
Kapnisi M, Mansfield C, Marijon C, et 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.
Chow A, Stuckey DJ, Kidher E, et 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.
Schobesberger S, Wright P, Poulet C, et al., 2017, beta(3) adrenergic signaling alters compartmentation and NO/cGMP/PDE2 signaling in heart failure, Publisher: ELSEVIER SCI LTD, Pages: 36-37, ISSN: 0022-2828
Schobesberger S, Wright P, Tokar S, et 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
Mawad D, Mansfield C, Lauto A, et 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.
Sanchez-Alonso JL, Bhargava A, O'Hara T, et 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.
Mansfield C, Mawad D, Perbellini F, et al., 2016, A novel conductive patch for application in cardiac tissue engineering, Cardiovascular Research, Vol: 111, Pages: S41-S41, ISSN: 1755-3245
Buyandelger B, Mansfield C, Luther P, et 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
Buyandelger B, Mansfield C, Kostin S, et 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.
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
Mansfield C, Buyandelger B, Kostin S, et al., 2014, The role of MIP1 in cardiac myocyte hypertrophy and survival, CARDIOVASCULAR RESEARCH, Vol: 103, ISSN: 0008-6363
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
Paur H, Wright PT, Sikkel MB, et 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
Mansfield C, West TG, Curtin NA, et 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, ISSN: 0021-9258
Song W, Dyer E, Stuckey D, et 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
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