Publications
346 results found
Bates J, McClymont D, Teh I, et al., 2017, Monte Carlo Simulations of Diffusion Weighted MRI in Myocardium: Validation and Sensitivity Analysis., IEEE Transactions on Medical Imaging, Vol: 36, Pages: 1316-1325, ISSN: 1558-254X
A model of cardiac microstructure and diffusion MRI is presented, and compared with experimental data from ex vivo rat hearts. The model includes a simplified representation of individual cells, with physiologically correct cell size and orientation, as well as intra- to extracellular volume ratio. Diffusion MRI is simulated using a Monte Carlo model and realistic MRI sequences. The results show good correspondence between the simulated and experimental MRI signals. Similar patterns are observed in the eigenvalues of the diffusion tensor, the mean diffusivity (MD) and the fractional anisotropy (FA). A sensitivity analysis shows that the diffusivity is the dominant influence on all three eigenvalues of the diffusion tensor, the MD and the FA. The area and aspect ratio of the cell cross-section affect the secondary and tertiary eigenvalues, and hence the FA. Within biological norms, the cell length, volume fraction of cells and rate of change of helix angle play a relatively small role in influencing tissue diffusion. Results suggest that the model could be used to improve understanding of the relationship between cardiac microstructure and diffusion MRI measurements, as well as in testing and refinement of cardiac diffusion MRI protocols.
Decher N, Ortiz-Bonnin B, Friedrich C, et al., 2017, Sodium permeable and "hypersensitive" TREK-1 channels cause ventricular tachycardia., EMBO Molecular Medicine, Vol: 9, Pages: 403-414, ISSN: 1757-4676
In a patient with right ventricular outflow tract (RVOT) tachycardia, we identified a heterozygous point mutation in the selectivity filter of the stretch-activated K2P potassium channel TREK-1 (KCNK2 or K2P2.1). This mutation introduces abnormal sodium permeability to TREK-1. In addition, mutant channels exhibit a hypersensitivity to stretch-activation, suggesting that the selectivity filter is directly involved in stretch-induced activation and desensitization. Increased sodium permeability and stretch-sensitivity of mutant TREK-1 channels may trigger arrhythmias in areas of the heart with high physical strain such as the RVOT We present a pharmacological strategy to rescue the selectivity defect of the TREK-1 pore. Our findings provide important insights for future studies of K2P channel stretch-activation and the role of TREK-1 in mechano-electrical feedback in the heart.
Kopton R, Rog-Zielinska E, Siedlecka U, et al., 2017, Optogenetic Modulation of Cardiomyocyte Excitability Ramona Kopton, 58th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 424A-424A, ISSN: 0006-3495
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Kong CHT, Rog-Zielinska EA, Orchard CH, et al., 2017, Diffusion in the Transverse-Axial Tubule System of Cardiac Myocytes, 61st Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 122A-122A, ISSN: 0006-3495
Aston D, Capel RA, Ford KL, et al., 2017, High resolution structural evidence suggests the Sarcoplasmic Reticulum forms microdomains with Acidic Stores (lysosomes) in the heart, Scientific Reports, Vol: 7, ISSN: 2045-2322
Nicotinic Acid Adenine Dinucleotide Phosphate (NAADP) stimulates calcium release from acidic stores such as lysosomes and is a highly potent calcium-mobilising second messenger. NAADP plays an important role in calcium signalling in the heart under basal conditions and following β-adrenergic stress. Nevertheless, the spatial interaction of acidic stores with other parts of the calcium signalling apparatus in cardiac myocytes is unknown. We present evidence that lysosomes are intimately associated with the sarcoplasmic reticulum (SR) in ventricular myocytes; a median separation of 20 nm in 2D electron microscopy and 3.3 nm in 3D electron tomography indicates a genuine signalling microdomain between these organelles. Fourier analysis of immunolabelled lysosomes suggests a sarcomeric pattern (dominant wavelength 1.80 μm). Furthermore, we show that lysosomes form close associations with mitochondria (median separation 6.2 nm in 3D studies) which may provide a basis for the recently-discovered role of NAADP in reperfusion-induced cell death. The trigger hypothesis for NAADP action proposes that calcium release from acidic stores subsequently acts to enhance calcium release from the SR. This work provides structural evidence in cardiac myocytes to indicate the formation of microdomains between acidic and SR calcium stores, supporting emerging interpretations of NAADP physiology and pharmacology in heart.
Kohl P, Quinn TA, 2016, Comparing maximum rate and sustainability of pacing by electrical versus mechanical stimulation in the Langendorff-perfused rabbit heart, Europace, Vol: 18, Pages: iv85-iv93, ISSN: 1532-2092
Aims: Mechanical stimulation (MS) represents a readily available, non-invasive means ofpacing the asystolic or bradycardic heart in patients, but benefits of MS at higher heart ratesare unclear. Our aim was to assess the maximum rate and sustainability of excitation by MSversus electrical stimulation (ES) in the isolated heart under normal physiological conditions.Methods and results: Trains of local MS or ES at rates exceeding intrinsic sinus rhythm(overdrive pacing; lowest pacing rates 2.50.5 Hz) were applied to the same mid-leftventricular free-wall site on the epicardium of Langendorff-perfused rabbit hearts. Stimulationrates were progressively increased, with a recovery period of normal sinus rhythm betweeneach stimulation period. Trains of MS caused repeated focal ventricular excitation from thesite of stimulation. The maximum rate at which MS maintained 1:1 capture was lower thanduring ES (4.20.2 vs. 5.90.2 Hz, respectively). At all overdrive pacing rates for whichrepetitive MS was possible, 1:1 capture was reversibly lost after a finite number of cycles,even though same-site capture by ES was maintained. The number of MS cycles until loss ofcapture decreased with rising stimulation rate. If interspersed with ES, the number of MS tofailure of capture was lower than for MS only.Conclusion: In this study, we demonstrate that the maximum pacing rate at which MS can besustained is lower than that for same-site ES in isolated heart, and that, in contrast to ES, thesustainability of successful 1:1 capture by MS is limited. The mechanism(s) of differences inMS versus ES pacing ability, potentially important for emergency heart rhythm management,are currently unknown, warranting further investigation.
Quinn TA, Camelliti P, Rog-Zielinska EA, et al., 2016, Electrotonic coupling of excitable and nonexcitable cells in the heart revealed by optogenetics, Proceedings of the National Academy of Sciences of USA, Vol: 113, Pages: 14852-14857, ISSN: 0027-8424
McClymont D, Teh I, Carruth E, et al., 2016, Evaluation of non-Gaussian diffusion in cardiac MRI., Magnetic Resonance in Medicine, Vol: 78, Pages: 1174-1186, ISSN: 1522-2594
PURPOSE: The diffusion tensor model assumes Gaussian diffusion and is widely applied in cardiac diffusion MRI. However, diffusion in biological tissue deviates from a Gaussian profile as a result of hindrance and restriction from cell and tissue microstructure, and may be quantified better by non-Gaussian modeling. The aim of this study was to investigate non-Gaussian diffusion in healthy and hypertrophic hearts. METHODS: Thirteen rat hearts (five healthy, four sham, four hypertrophic) were imaged ex vivo. Diffusion-weighted images were acquired at b-values up to 10,000 s/mm(2) . Models of diffusion were fit to the data and ranked based on the Akaike information criterion. RESULTS: The diffusion tensor was ranked best at b-values up to 2000 s/mm(2) but reflected the signal poorly in the high b-value regime, in which the best model was a non-Gaussian "beta distribution" model. Although there was considerable overlap in apparent diffusivities between the healthy, sham, and hypertrophic hearts, diffusion kurtosis and skewness in the hypertrophic hearts were more than 20% higher in the sheetlet and sheetlet-normal directions. CONCLUSION: Non-Gaussian diffusion models have a higher sensitivity for the detection of hypertrophy compared with the Gaussian model. In particular, diffusion kurtosis may serve as a useful biomarker for characterization of disease and remodeling in the heart. Magn Reson Med, 2016. © 2016 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Brandenburg S, Kohl T, Williams GS, et al., 2016, Axial tubule junctions control rapid calcium signaling in atria., Journal of Clinical Investigation, Vol: 126, Pages: 3999-4015, ISSN: 1558-8238
The canonical atrial myocyte (AM) is characterized by sparse transverse tubule (TT) invaginations and slow intracellular Ca2+ propagation but exhibits rapid contractile activation that is susceptible to loss of function during hypertrophic remodeling. Here, we have identified a membrane structure and Ca2+-signaling complex that may enhance the speed of atrial contraction independently of phospholamban regulation. This axial couplon was observed in human and mouse atria and is composed of voluminous axial tubules (ATs) with extensive junctions to the sarcoplasmic reticulum (SR) that include ryanodine receptor 2 (RyR2) clusters. In mouse AM, AT structures triggered Ca2+ release from the SR approximately 2 times faster at the AM center than at the surface. Rapid Ca2+ release correlated with colocalization of highly phosphorylated RyR2 clusters at AT-SR junctions and earlier, more rapid shortening of central sarcomeres. In contrast, mice expressing phosphorylation-incompetent RyR2 displayed depressed AM sarcomere shortening and reduced in vivo atrial contractile function. Moreover, left atrial hypertrophy led to AT proliferation, with a marked increase in the highly phosphorylated RyR2-pS2808 cluster fraction, thereby maintaining cytosolic Ca2+ signaling despite decreases in RyR2 cluster density and RyR2 protein expression. AT couplon "super-hubs" thus underlie faster excitation-contraction coupling in health as well as hypertrophic compensatory adaptation and represent a structural and metabolic mechanism that may contribute to contractile dysfunction and arrhythmias.
de Tombe PP, Kohl P, 2016, Which way to grow? Force over time may be the heart's Dao de jing., Global Cardiology Science & Practice, Vol: 2016, ISSN: 2305-7823
Genetic cardiomyopathy manifests as either a hypertrophic or dilated phenotype. However, molecular mechanisms that determine which disease pathway emerges in patients is largely unknown. Work from the Molkentin laboratory published in the May issue of the journal Cell provides novel insights into this fundamental question. The investigators found that sarcomeric mutations associated with a reduced muscle contraction-time integral resulted in a dilated cardiomyopathy, while mutations associated with an increase in this parameter were associated with a hypertrophic phenotype. The molecular cellular cues that orchestrate which cardiomyopathic pathway ensues appear to be the signal transduction pathways involving the molecules MEK1 and ERK1/2. The identified signals driving overall growth of the heart, on the either hand, were found to involve Calcineurin and NFAT. These findings may help improve treatment strategies aimed to combat familial cardiopathy and, moreover, pave the way to the development of novel personalized medicine based therapy by using cardiac cells that are derived from individual patient’s induced pluripotent stem (iPS) cells.
Woods C, Shang C, Taghavi F, et al., 2016, In vivo post-cardiac arrest myocardial dysfunction is supported by camkii-mediated calcium long-term potentiation and mitigated by Alda-1, an agonist of aldehyde dehydrogenase type 2, Circulation, Vol: 134, Pages: 961-977, ISSN: 0009-7322
BACKGROUND: -Survival after sudden cardiac arrest is limited by post-arrest myocardial dysfunction but understanding of this phenomenon is constrained by lack of data from a physiological model of disease. In this study, we established an in vivo model of cardiac arrest and resuscitation, characterized the biology of the associated myocardial dysfunction, and tested novel therapeutic strategies. METHODS: -We developed rodent models of in vivo post-arrest myocardial dysfunction using extra-corporeal membrane oxygenation (ECMO) resuscitation followed by invasive hemodynamics measurement. In post-arrest isolated cardiomyocytes, we assessed mechanical load and Ca(2+) induced Ca(2+) release (CICR) simultaneously using the micro-carbon-fiber technique and observed reduced function and myofilament calcium sensitivity. We used a novel-designed fiber optic catheter imaging system, and a genetically encoded calcium sensor GCaMP6f, to image CICR in vivo RESULTS: -We found potentiation of CICR in isolated cells from this ECMO model and also in cells isolated from an ischemia-reperfusion Langendorff model perfused with oxygenated blood from an arrested animal, but not when reperfused in saline. We established that CICR potentiation begins in vivo The augmented CICR observed post-arrest was mediated by the activation of Ca(2+)/calmodulin kinase II (CaMKII). Increased phosphorylation of CaMKII, phospholamban and ryanodine receptor 2 (RyR2) was detected in the post-arrest period. Exogenous adrenergic activation in vivo recapitulated Ca(2+) potentiation but was associated with lesser CaMKII activation. Since oxidative stress and aldehydic adduct formation were high post arrest, we tested a small molecule activator of aldehyde dehydrogenase type 2, Alda-1, which reduced oxidative stress, restored calcium and CaMKII homeostasis, and improved cardiac function and post-arrest outcome in vivo CONCLUSIONS: -Cardiac arrest and reperfusion lead to CaMKII activation and calcium long-term pot
Teh I, McClymont D, Burton RA, et al., 2016, Resolving Fine Cardiac Structures in Rats with High-Resolution Diffusion Tensor Imaging, Scientific Reports, Vol: 6, ISSN: 2045-2322
Cardiac architecture is fundamental to cardiac function and can be assessed non-invasively with diffusion tensor imaging (DTI). Here, we aimed to overcome technical challenges in ex vivo DTI in order to extract fine anatomical details and to provide novel insights in the 3D structure of the heart. An integrated set of methods was implemented in ex vivo rat hearts, including dynamic receiver gain adjustment, gradient system scaling calibration, prospective adjustment of diffusion gradients, and interleaving of diffusion-weighted and non-diffusion-weighted scans. Together, these methods enhanced SNR and spatial resolution, minimised orientation bias in diffusion-weighting, and reduced temperature variation, enabling detection of tissue structures such as cell alignment in atria, valves and vessels at an unprecedented level of detail. Improved confidence in eigenvector reproducibility enabled tracking of myolaminar structures as a basis for segmentation of functional groups of cardiomyocytes. Ex vivo DTI facilitates acquisition of high quality structural data that complements readily available in vivo cardiac functional and anatomical MRI. The improvements presented here will facilitate next generation virtual models integrating micro-structural and electro-mechanical properties of the heart.
Gourdie RG, Dimmeler S, Kohl P, 2016, Novel therapeutic strategies targeting fibroblasts and fibrosis in heart disease, Nature Reviews Drug Discovery, Vol: 15, Pages: 620-638, ISSN: 1474-1784
Our understanding of cardiac fibroblast functions has moved beyond their roles in heart structure and extracellular matrix generation, and now includes contributions to paracrine, mechanical and electrical signalling during ontogenesis and normal cardiac activity. Fibroblasts have central roles in pathogenic remodelling during myocardial ischaemia, hypertension and heart failure. As key contributors to scar formation, they are crucial for tissue repair after interventions including surgery and ablation. Novel experimental approaches targeting cardiac fibroblasts are promising potential therapies for heart disease. Indeed, several existing drugs act, at least partially, through effects on cardiac connective tissue. This Review outlines the origins and roles of fibroblasts in cardiac development, homeostasis and disease; illustrates the involvement of fibroblasts in current and emerging clinical interventions; and identifies future targets for research and development.
Teh I, Burton RA, McClymont D, et al., 2016, Mapping cardiac microstructure of rabbit heart in different mechanical states by high resolution diffusion tensor imaging: A proof-of-principle study., Progress in Biophysics and Molecular Biology, Vol: 121, Pages: 85-96, ISSN: 1873-1732
Myocardial microstructure and its macroscopic materialisation are fundamental to the function of the heart. Despite this importance, characterisation of cellular features at the organ level remains challenging, and a unifying description of the structure of the heart is still outstanding. Here, we optimised diffusion tensor imaging data to acquire high quality data in ex vivo rabbit hearts in slack and contractured states, approximating diastolic and systolic conditions. The data were analysed with a suite of methods that focused on different aspects of the myocardium. In the slack heart, we observed a similar transmural gradient in helix angle of the primary eigenvector of up to 23.6°/mm in the left ventricle and 24.2°/mm in the right ventricle. In the contractured heart, the same transmural gradient remained largely linear, but was offset by up to +49.9° in the left ventricle. In the right ventricle, there was an increase in the transmural gradient to 31.2°/mm and an offset of up to +39.0°. The application of tractography based on each eigenvector enabled visualisation of streamlines that depict cardiomyocyte and sheetlet organisation over large distances. We observed multiple V- and N-shaped sheetlet arrangements throughout the myocardium, and insertion of sheetlets at the intersection of the left and right ventricle. This study integrates several complementary techniques to visualise and quantify the heart's microstructure, projecting parameter representations across different length scales. This represents a step towards a more comprehensive characterisation of myocardial microstructure at the whole organ level.
Odening KE, Kohl P, 2016, Follow the white rabbit: Experimental and computational models of the rabbit heart provide insights into cardiac (patho-) physiology, Progress in Biophysics and Molecular Biology, Vol: 121, Pages: 75-76, ISSN: 1873-1732
Rog-Zielinska EA, Johnston CM, O'Toole E, et al., 2016, Electron tomography of rabbit cardiomyocyte three-dimensional ultrastructure, Progress in Biophysics & Molecular Biology, Vol: 121, Pages: 77-84, ISSN: 0079-6107
The field of cardiovascular research has benefitted from rapid developments in imaging technology over the last few decades. Accordingly, an ever growing number of large, multidimensional data sets have begun to appear, often challenging existing pre-conceptions about structure and function of biological systems. For tissue and cell structure imaging, the move from 2D section-based microscopy to true 3D data collection has been a major driver of new insight. In the sub-cellular domain, electron tomography is a powerful technique for exploration of cellular structures in 3D with unparalleled fidelity at nanometer resolution.Electron tomography is particularly advantageous for studying highly compartmentalised cells such as cardiomyocytes, where elaborate sub-cellular structures play crucial roles in electrophysiology and mechanics. Although the anatomy of specific ultra-structures, such as dyadic couplons, has been extensively explored using 2D electron microscopy of thin sections, we still lack accurate, quantitative knowledge of true individual shape, volume and surface area of sub-cellular domains, as well as their 3D spatial interrelations; let alone of how these are reshaped during the cycle of contraction and relaxation. Here we discuss and illustrate the utility of ET for identification, visualisation, and analysis of 3D cardiomyocyte ultrastructures such as the T-tubular system, sarcoplasmic reticulum, mitochondria and microtubules.
Quinn T, Kohl P, 2016, Rabbit models of cardiac mechano-electric and mechano-mechanical coupling, Progress in Biophysics and MolecularBiology, Vol: 121, Pages: 110-122, ISSN: 0079-6107
Cardiac auto-regulation involves integrated regulatory loops linking electrics and mechanics in the heart. Whereas mechanical activity is usually seen as ‘the endpoint’ of cardiac auto-regulation, it is important to appreciate that the heart would not function without feed-back from the mechanical environment to cardiac electrical (mechano-electric coupling, MEC) and mechanical (mechano-mechanical coupling, MMC) activity. MEC and MMC contribute to beat-by-beat adaption of cardiac output to physiological demand, and they are involved in various pathological settings, potentially aggravating cardiac dysfunction. Experimental and computational studies using rabbit as a model species have been integral to the development of our current understanding of MEC and MMC. In this paper we review this work, focusing on physiological and pathological implications for cardiac function.
Odening KE, Kohl P, 2016, Editorial to “Disturbances of cardiac wavelength and repolarization precede torsade de pointes and ventricular fibrillation in langendorff perfused rabbit hearts” by Luc Hondeghem ∗: It is difficult to make predictions, especially about the future∗: Thoughts about forecasting cardiotoxicity of pharmacological interventions, Progress in Biophysics and Molecular Biology, Vol: 121, Pages: 1-2, ISSN: 0079-6107
Edelmann JC, Jones L, Peyronnet R, et al., 2016, A Bioreactor to Apply Multimodal Physical Stimuli to Cultured Cells, Methods in Molecular Biology, Vol: 1502, Pages: 21-33, ISSN: 1940-6029
Cells residing in the cardiac niche are constantly experiencing physical stimuli, including electrical pulses and cyclic mechanical stretch. These physical signals are known to influence a variety of cell functions, including the secretion of growth factors and extracellular matrix proteins by cardiac fibroblasts, calcium handling and contractility in cardiomyocytes, or stretch-activated ion channels in muscle and non-muscle cells of the cardiovascular system. Recent progress in cardiac tissue engineering suggests that controlled physical stimulation can lead to functional improvements in multicellular cardiac tissue constructs. To study these effects, aspects of the physical environment of the myocardium have to be mimicked in vitro. Applying continuous live imaging, this protocol demonstrates how a specifically designed bioreactor system allows controlled exposure of cultured cells to cyclic stretch, rhythmic electrical stimulation, and controlled fluid perfusion, at user-defined temperatures.
Nisbet AM, Camelliti P, Walker NL, et al., 2016, Prolongation of atrio-ventricular node conduction in a rabbit model of ischaemic cardiomyopathy: Role of fibrosis and connexin remodelling, Journal of Molecular and Cellular Cardiology, Vol: 94, Pages: 54-64, ISSN: 1095-8584
Conduction abnormalities are frequently associated with cardiac disease, though the mechanisms underlying the commonly associated increases in PQ interval are not known. This study uses a chronic left ventricular (LV) apex myocardial infarction (MI) model in the rabbit to create significant left ventricular dysfunction (LVD) 8 weeks post-MI. In vivo studies established that the PQ interval increases by approximately 7 ms (10%) with no significant change in average heart rate. Optical mapping of isolated Langendorff perfused rabbit hearts recapitulated this result: time to earliest activation of the LV was increased by 14 ms (16%) in the LVD group. Intra-atrial and LV transmural conduction times were not altered in the LVD group. Isolated AVN preparations from the LVD group demonstrated a significantly longer conduction time (by approximately 20 ms) between atrial and His electrograms than sham controls across a range of pacing cycle lengths. This difference was accompanied by increased effective refractory period and Wenckebach cycle length, suggesting significantly altered AVN electrophysiology post-MI. The AVN origin of abnormality was further highlighted by optical mapping of the isolated AVN. Immunohistochemistry of AVN preparations revealed increased fibrosis and gap junction protein (connexin43 and 40) remodelling in the AVN of LVD animals compared to sham. A significant increase in myocyte–non-myocyte connexin co-localization was also observed after LVD. These changes may increase the electrotonic load experienced by AVN muscle cells and contribute to slowed conduction velocity within the AVN.
Wang K, Climent A, Gavaghan D, et al., 2016, Room Temperature vs Ice Cold - Temperature Effects on Cardiac Cell Action Potential, 60th Annual Meeting of the Biophysical-Society, Publisher: CELL PRESS, Pages: 587A-587A, ISSN: 0006-3495
Ongstad E, Kohl P, 2016, Fibroblast-myocyte coupling in the heart: Potential relevance for therapeutic interventions, JOURNAL OF MOLECULAR AND CELLULAR CARDIOLOGY, Vol: 91, Pages: 238-246, ISSN: 0022-2828
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Peyronnet R, Nerbonne JM, Kohl P, 2016, Cardiac Mechano-Gated Ion Channels and Arrhythmias, Circulation Research, Vol: 118, Pages: 311-329, ISSN: 1524-4571
Mechanical forces will have been omnipresent since the origin of life, and living organisms have evolved mechanisms to sense, interpret, and respond to mechanical stimuli. The cardiovascular system in general, and the heart in particular, is exposed to constantly changing mechanical signals, including stretch, compression, bending, and shear. The heart adjusts its performance to the mechanical environment, modifying electrical, mechanical, metabolic, and structural properties over a range of time scales. Many of the underlying regulatory processes are encoded intracardially and are, thus, maintained even in heart transplant recipients. Although mechanosensitivity of heart rhythm has been described in the medical literature for over a century, its molecular mechanisms are incompletely understood. Thanks to modern biophysical and molecular technologies, the roles of mechanical forces in cardiac biology are being explored in more detail, and detailed mechanisms of mechanotransduction have started to emerge. Mechano-gated ion channels are cardiac mechanoreceptors. They give rise to mechano-electric feedback, thought to contribute to normal function, disease development, and, potentially, therapeutic interventions. In this review, we focus on acute mechanical effects on cardiac electrophysiology, explore molecular candidates underlying observed responses, and discuss their pharmaceutical regulation. From this, we identify open research questions and highlight emerging technologies that may help in addressing them.
Rog-Zielinska EA, Norris RA, Kohl P, et al., 2016, The living scar - cardiac fibroblasts and the injured heart, Trends in Molecular Medicine, Vol: 22, Pages: 99-114, ISSN: 1471-4914
Cardiac scars, often dubbed ‘dead tissue’, are very much alive, with heterocellular activity contributing to the maintenance of structural and mechanical integrity following heart injury. To form a scar, non-myocytes such as fibroblasts are recruited from intra- and extra-cardiac sources. Fibroblasts perform important autocrine and paracrine signaling functions. They also establish mechanical and, as is increasingly evident, electrical junctions with other cells. While fibroblasts were previously thought to act simply as electrical insulators, they may be electrically connected among themselves and, under some circumstances, to other cells including cardiomyocytes. A better understanding of these biophysical interactions will help to target scar structure and function, and will facilitate the development of novel therapies aimed at modifying scar properties for patient benefit.
Kohl P, Tsyvian PB, Tsaturyan AK, et al., 2016, Mechano-Electric Heterogeneity Of The Myocardium As A Paradigm Of Its Function, Progress in Biophysics & Molecular Biology, Vol: 120, Pages: 249-254, ISSN: 0079-6107
Myocardial heterogeneity is well appreciated and widely documented, from sub-cellular to organ levels. This paper reviewssignificant achievements of the group, led by Professor Vladimir S. Markhasin, Russia, who was one of the pioneers in studyingand interpreting the relevance of cardiac functional heterogeneity
Lohezic M, Bollensdorff C, Korn M, et al., 2015, Optimized radiofrequency coil setup for MR examination of living isolated rat hearts in a horizontal 9.4T magnet, Magnetic Resonance in Medicine, Vol: 73, Pages: 2398-2405, ISSN: 1522-2594
Purpose: (i) To optimize an MR-compatible organ perfusionsetup for the nondestructive investigation of isolated rat heartsby placing the radiofrequency (RF) coil inside the perfusionchamber; (ii) to characterize the benefit of this system for diffusiontensor imaging and proton (1H-) MR spectroscopy.Methods: Coil quality assessment was conducted both on thebench, and in the magnet. The benefit of the new RF-coil wasquantified by measuring signal-to-noise ratio (SNR), accuracy,and precision of diffusion tensor imaging/error in metaboliteamplitude estimation, and compared to an RF-coil placedexternally to the perfusion chamber.Results: The new design provided a 59% gain in signal-to-noiseratio on a fixed rat heart compared to using an external resonator,which found reflection in an improvement of living heart dataquality, compared to previous external resonator studies. Thisresulted in 14–29% improvement in accuracy and precision ofdiffusion tensor imaging. The Cramer–Rao lower bounds formetabolite amplitude estimations were up to 5-fold smaller.Conclusion: Optimization of MR-compatible perfusion equipmentadvances the study of rat hearts with improved signal-tonoiseratio performance, and thus improved accuracy/precision
Wang K, Lee P, Mirams GR, et al., 2015, Cardiac tissue slices: preparation, handling, and successful optical mapping, AMERICAN JOURNAL OF PHYSIOLOGY-HEART AND CIRCULATORY PHYSIOLOGY, Vol: 308, Pages: H1112-H1125, ISSN: 0363-6135
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Lau DH, Volders PGA, Kohl P, et al., 2015, Opportunities and challenges of current electrophysiology research: a plea to establish 'translational electrophysiology' curricula, EUROPACE, Vol: 17, Pages: 825-833, ISSN: 1099-5129
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Wang K, Mu-u-Min R, Terrar D, et al., 2015, Electrophysiology of Cardiac Tissue Slices before, during, and after Stretch
Bates J, Teh I, Kohl P, et al., 2015, Sensitivity Analysis of Diffusion Tensor MRI in Simulated Rat Myocardium, 8th International Conference on Functional Imaging and Modeling of the Heart(FIMH), Publisher: SPRINGER-VERLAG BERLIN, Pages: 120-128, ISSN: 0302-9743
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