Dynamic regulation of subcellular calcium handling in the atria:modifying effects of stretch and adrenergic stimulation

Atrial fibrillation is the fast and irregular heart rate that occurs when the upper chambers of the heart experience chaotic electrical activation. Three main factors contribute to the development of this disease: triggers, substrate and modifying factors. An arrhythmia is thus like a fire that needs a spark (Trigger) to ignite a pile of wood (Substrate) and depends on the humidity or accelerants (modifying factors) to burn faster or slower. This body of work takes a closer look at such modifying factors. The major finding of this thesis is that stretching atrial heart muscle cells releases Calcium ions from storage spaces within each cell. If these Calcium release events get frequent enough they can act as triggers for the arrhythmia. The thickness of the atrial muscle is heterogeneous, thus filling the atrium with blood distends thinner parts stronger than ticker portions. The varying degree of stretch might stimulate Calcium release predominantly from myocytes in thinner regions of the atria. This heterogeneity in spontaneous Calcium release can modify also the substrate. A comparable effect of stretch was previously described in the heart’s main chambers. However, it appears that the in the atria it depends on another mechanism, which could serve as a treatment target that mainly acts on the atria without negatively affecting the ventricle

Experimental and computational biomedicine : Russian Conference with International Participation in memory of Professor Vladimir S. Markhasin : abstract book

Toward 100 Anniversary of I. P. Pavlov's Physiological Society.The volume contains the presentations that were made during Russian conference with international participation "Experimental and Computational Biomedicine" dedicated to corresponding member of RAS V.S. Markhasin (Ekaterinburg, April 10‒12, 2016). The main purpose of the conference is the discussion of the current state of experimental and theoretical research in biomedicine. For a wide range of scientists, as well as for lecturers, students of the biological and medical high schools.Сборник содержит тезисы докладов, представленных на российской конференции с международным участием «Экспериментальная и компьютерная биомедицина», посвященной памяти члена‐корреспондента РАН В. С. Мархасина (г. Екатеринбург, 10‒12 апреля 2016 г.). Основной целью конференции является обсуждение современного состояния экспериментальных и теоретических исследований в области биомедицины. Сборник предназначен для ученых, преподавателей, студентов и аспирантов биологического и медицинского профиля.МАРХАСИН ВЛАДИМИР СЕМЕНОВИЧ (1941-2015)/ MARKHASIN VLADIMIR SEMENOVICH (1941-2015). [3] PROGRAMM COMMITTEE. [5] ORGANIZING COMMITTEE. [6] KEYNOTE SPEAKERS. [7] CONTENTS. [9] PLENARY LECTURES. [10] Fedotov S. Non-Markovian random walks and anomalous transport in biology. [10] Hoekstra A. Multiscale modelling in vascular disease. [10] Kohl P. Systems biology of the heart: why bother? [10] Meyerhans A. On the regulation of virus infection fates. [11] Panfilov A.V., Dierckx H., Kazbanov I., Vandersickel N. Systems approach to studying mechanisms of ventricular fibrillationusing anatomically accurate modeling. [11] Revishvili A.S. Atrial fibrillation. Noninvasive diagnostic and treatment:from fundamental studies to clinical practice. [12] Rice J. Life sciences research at IBM. [12] Roshchevskaya I.M., Smirnova S., Roshchevsky M.P. Regularities of the depolarization of an atria:an experimental comparative-physiological study. [12] Rusinov V.L., Chupahin O.N., Charushin V.N Scientific basis for development of antiviral drugs. [13] Solovyova O.E. Tribute Lecture. Mechano-electric heterogeneity of the myocardiumas a paradigm of its function. [13] Veksler V. Myocardial energy starvation in chronic heart failure:perspectives for metabolic therapy. [13] Wladimiroff J.W. Fetal cardiac assessment using new methodsof ultrasound examination. [14] Yushkov B.G., Chereshnev V.A. The important questions of regeneration theory. [14] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] EXPERIMENTAL AND COMPUTATIONAL MODELS IN CARDIOVASCULARPHYSIOLOGY AND CARDIOLOGY. [15] Arteyeva N. T-wave area along with Tpeak-Tend interval is the most accurateindex of the dispersion of repolarization. [15] Borodin N., Iaparov B.Y., Moskvin A. Mathematical modeling of the calmodulin effect on the RyR2 gating. [15] Dokuchaev A., Katsnelson L.B., Sulman T.B., Shikhaleva E.V., Vikulova N.A. Contribution of cooperativity to the mechano-calcium feedbacksin myocardium. Experimental discrepancy and mathematicalapproach to overcome it. [16] Elman K.A., Filatova D.Y., Bashkatova Y.V., Beloschenko D.V. The stochastic and chaotic estimation of parametersof cardiorespiratory system of students of Ugra. [16] Erkudov V.O., Pugovkin A.P., Verlov N.A., Sergeev I.V., Ievkov S.A., Mashood S., Bagrina J.V. Characteristics of the accuracy of calculation of values of systemic blood pressure using transfer functions in experimental blood loss and its compensation. [16] Ermolaev P., Khramykh T.Mechanisms of cardiodepression after 80% liver resection in rats. [17] Filatova O.E., Rusak S.N., Maystrenko E.V., Dobrynina I.Y. Aging dynamics of cardio-vascular parameters аboriginal systemand alien population of the Russian North. [17] Frolova S., Agladze K.I., Tsvelaya V., Gaiko O. Photocontrol of voltage-gated ion channel activity by azobenzenetrimethylammonium bromide in neonatal rat cardiomyocytes. [18] Gorbunov V.S., Agladze K.I., Erofeev I.S. The application of C-TAB for excitation propagation photocontrolin cardiac tissue. [18] Iribe G. Localization of TRPC3 channels estimated by in-silicoand cellular functional experiments. [19] Kachalov V.N., Tsvelaya V., Agladze K.I. Conditions of the spiral wave unpinning from the heterogeneitywith different boundary conditions in a model of cardiac tissue. [19] Kalita I., Nizamieva A.A., Tsvelaya V., Kudryashova N., Agladze K.I. The influence of anisotropy on excitation wave propagationin neonatal rat cardiomyocytes monolayer. [19] Kamalova Y. The designing of vectorcardiograph prototype. [20] Kapelko V., Shirinsky V.P., Lakomkin V., Lukoshkova E., Gramovich V.,Vyborov O., Abramov A., Undrovinas N., Ermishkin V. Models of chronic heart failure with acute and gradual onset. [20] Khassanov I., Lomidze N.N., Revishvili A.S. Remote Patient Monitoring and Integration of Medical Data. [20] Kislukhin V. Markov chain for an indicator passing throughoutcardio-vascular system (CVS). [21] Konovalov P.V., Pravdin S., Solovyova O.E., Panfilov A.V. Influence of myocardial heterogeneity on scroll wave dynamicsin an axisymmetrical anatomical model of the left ventricle of thehuman heart. [21] Koshelev A., Pravdin S., Ushenin K.S., Bazhutina A.E. An improved analytical model of the cardiac left ventricle. [22] Lookin O., Protsenko Y.L. Sex-related effects of stretch on isometric twitch and Ca2+ transientin healthy and failing right ventricular myocardiumof adult and impuberal rats. [22] Moskvin A. Electron-conformational model of the ligand-activated ion channels. [22] Nezlobinsky T., Pravdin S., Katsnelson L.B. In silico comparison of the electrical propagation wave alongmyocardium fibers in the left ventricle wall vs. isolation. [23] Nigmatullina R.R., Zemskova S.N., Bilalova D.F., Mustafin A.A., Kuzmina O.I., Chibireva M.D., Nedorezova R.S. Valid method for estimation of pulmonary hypertention degreein children. [23] Parfenov A. Mathematical modeling of the cardiovascular systemunder the influence of environmental factors. [24] Pimenov V.G., Hendy A. Adaptivity of the alternating direction method for fractional reactiondiffusion equation with delay effects in electrocardiology. [24] Podgurskaya A.D., Krasheninnikova A., Tsvelaya V., Kudryashova N., Agladze K.I. Influence of alcohols on excitation wave propagationin neonatal rat ventricular cardiomyocyte monolayer. [24] Pravdin S. A mathematical model of the cardiac left ventricle anatomy and morphology. [24] Seemann G. Cause and effects of cardiac heterogeneity:insights from experimental and computational models. [25] Seryapina A.A., Shevelev O.B. Basic metabolomic patterns in early hypertensive rats: MRI study. [25] Shestakov A.P., Vasserman I.N., Shardakov I.N. Modeling of cardiac arrhythmia generation caused bypathological distribution of myocardial conductivity. [26] Shutko A.V., Gorbunov V.S., Nizamieva A.A., Guriya K.G., Agladze K.I. Contractile micro-constructs from cardiac tissue culturefor the research of autowave propagation in excitable systems. [26] Simakov S., Gamilov T., Kopylov Ph. Computational study of the haemodynamic significanceof the stenosis during multivessel coronary disease. [27] Syomin F., Zberiya M.V. A numerical simulation of changes in the performance of the leftventricle of the heart under various hemodynamic conditions. [27] Tsaturyan A. A simple model of cardiac muscle:mechanics, actin-myosin interaction and Ca-activation. [27] Tsvelaya V., Krasheninnikova A., Kudryashova N., Agladze K.I. Calcium-current dominated upstroke in severe hyperkalemia. [28] Ushenin K.S., Pravdin S., Chumarnaya T.V., Alueva Y.S., Solovyova O.E. Dynamics of scroll wave filaments in personalized modelsof the left ventricle of the human heart. [28] Vasserman I.N., Shardakov I.N., Shestakov A.P. Deriving of macroscopic intracellular conductivity of deformedmyocardium based on its microstructure. [28] Vassilevski Y.V., Pryamonosov R., Gamilov T. Personalized 3D models and applications. [29] Zun P.S., Hoekstra A., Anikina T.S. First results of fully coupled 3D models of in-stent restenosis. [29] BIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELSSBIOMECHANICS. EXPERIMENTAL AND MATHEMATICAL MODELS. EXPERIMENTAL AND MATHEMATICAL MODELS. [30] Balakin A., Kuznetsov D., Protsenko Y.L. The ‘length-tension’ loop in isolated myocardial preparations of theright ventricle of normal and hypertrophied hearts of male rats. [30] Belousova M.D., Kruchinina A.P., Chertopolokhov V.A. Automatic control model of the three-tier arm type manipulatorin the aimed-movement task. [30] Berestin D.K., Bazhenova A.E., Chernikov N.A., Vokhmina Y.V. Mathematical modeling of dynamics of development of Parkinson'sdisease on the tremor parameters. [31] Dubinin A.L., Nyashin Y.I., Osipenko M.A. Development of the biomechanical approach to tooth movementunder the orthodontic treatment. [31] Galochkina T., Volpert V. Reaction-diffusion waves in mathematical model of bloodcoagulation. [31] Golov A.V., Simakov S., Timme E.A. Mathematical modeling of alveolar ventilationand gas exchange during treadmill stress tests. [32] Gurev V., Rice J. Strain prediction in 3D finite element models of cardiac mechanics. [32] Kamaltdinov M.R. Simulation of digestion processes in antroduodenum:food particles dissolution in consideration of functional disorders. [33] Khamzin S., Kursanov A., Solovyova O.E. Load-dependence of the electromechanical function of myocardiumin a 1D tissue model. [33] Khokhlova A., Iribe G., Solovyova O.E Transmural gradient in mechanical properties of isolatedsubendocardial and subepicardial cardiomyocytes. [33] Kruchinin P.A. Optimal control problem and indexesof stabilometric "test with the visual step input". [34] Kruchinina A.P., Yakushev A.G. A study of the edge segments of saccadic eye trajectory. [34] Kursanov A., Khamzin S., Solovyova O.E. Load-dependence of intramyocardial slow force responsein heterogeneous myocardium. [35] Lisin R.V., Balakin A., Protsenko Y.L. Experimental study of the intramyocardial slow force response. [35] Melnikova N.B., Hoekstra A. The mechanics of a discrete multi-cellular model of arterial in‐stent restenosis. [35] Murashova D.S., Murashov S.A., Bogdan O.P., Muravieva O.V., Yugova S.O. Modelling of soft tissue deformation for static elastometry. [36] Nikitin V.N., Tverier V.M., Krotkikh A.A. Occlusion correction based on biomechanical modelling. [36] Nyashin Y.I., Lokhov V.A. Development of the “Virtual physiological human” concept. [37] Shulyatev A.F., Akulich Y.V., Akulich A.Y., Denisov A.S. 3D FEA simulation of the proximal human femur. [37] Smoluk A.T., Smoluk L.T., Balakin A., Protsenko Y.L., Lisin R.V. Modelling viscoelastic hysteresis of passive myocardial sample. [37] Svirepov P.I. Mathematical modeling of the left atria mechanical actionwith mitral regurgitation. [38] Svitenkov A., Rekin O., Hoekstra A. Accuracy of 1D blood flow simulations in relation to level of detailof the arterial tree model. [38] Tsinker M. Mathematical modelling of airflow in human respiratory tract. [39] Wilde M.V. Influence of artificial initial and boundary conditionsin biomechanical models of blood vessels. [39] ELECTROPHYSIOLOGY. EXPERIMENTAL AND COMPUTATIONAL MODELS. CLINICAL STUDIES. [40] Agladze K.I., Agladze N.N. Arrhythmia modelling in tissue culture. [40] Golovko V., Gonotkov M.A. Pharmacological analysis of transmembrane action potential'smorphology of myoepitelial cells in the spontaneously beating heartof ascidia Styela rustica. [40] Gonotkov M.A., Golovko V. The crucial role of the rapidly activating component of outwarddelayed rectifier K-current (IKr) in pig sinoauricular node (SAN). [40] Danilov A.A. Numerical methods for electrocardiography modelling. [41] Kolomeyets N.L., Roshchevskaya I.M. The electrical resistivity of a segment of the tail, lungs, liver,intercostal muscles of grass snakes during cooling. [41] Kharkovskaia E., Zhidkova N., Mukhina I.V., Osipov G.V. Role of TRPC1 channels in the propagation of electrical excitationin the isolated rat heart. [42] Lubimceva T.A., Lebedeva V.K., Trukshina M.A., Lyasnikova E.A., Lebedev D.S. Ventricular lead position and mechanical dyssynchronyin response to cardiac resynchronization therapy. [42] Poskina T.Y., Shakirova L.S., Klyus L.G., Eskov V.V. Stochastics and chaotic analysis of electromyogramand electroencefalogramm. [42] Prosheva V.I. New insights into the pacemaker and conduction systemcells organization in the adult avian heart. [43] Suslonova O., Smirnova S., Roshchevskaya I.M. Cardioelectric field in rats with experimental pulmonaryhypertension during ventricular depolarization. [43] Syunyaev R.A., Karpaev A.A., Aliev R.R. Simulation of the fibroblasts effect on synchronizationand rhythmogenesis in the sinoatrial node. [44] Zorin N.M., Ryvkin A.М., Moskvin A. Cooperation of membrane and calcium oscillatorsin sinoatrial node cells. [44] EXPERIMENTAL AND COMPUTATIONAL MODELS IN IMMUNOLOGY. [45] Bocharov G. Systems approach to modelling the "virus-host organism" interactionin infectious diseases. [45] Brilliant S.A. Impact of immobilization stress on change of protein fractionshemoglobin of bone marrow in rats. [45] Bykova M. The features of biochemical properties of extracellular matrix of bonemarrow in rats in conditions which stimulate granulocytopoiesis. [45] Chigvintsev V.M. A mathematical model of the functioning and mutual regulation ofthe immune and neuroendocrine systems in response to viralexposure under the impact of environmental factors, taking intoaccount the evolution of synthetic function impairment. [46] Khramtsova Y. The role of mast cells in the regulation of repair testicles. [46] Novikov M.Y., Kim A.V. Simulation of immune processes using Bio-Medical Software Package. [47] Polevshchikov A.V., Bondar A.V., Gumovskaya J.P. Modelling of t cell extravasation into a lymph node:from morphological basics towards clonal selection theory. [47] Tuzankina I.A., Sarkisyan N., Bolkov M., Tihomirov L.B., Bass E.A. Oral and maxillofacial manifestationsof primary immunodeficiency syndroms. [47] Zaitsev S.V., Polevshchikov A.V. Evaluation of probabilities of antigen recognition by T-lymphocytesin the lymph node: a mathematical model. [48] MOLECULAR BASIS OF BIOLOGICAL MOTILITY. [49] Bershitsky S.Y., Nabiev S., Kopylova G., Shchepkin D., Matyushenko A.M., Koubassova N.A., Levitsky D.I., Tsaturyan A. Mutations in the central part of tropomyosin molecule affectthe actomyosin interaction. [49] Borovkov D.I., Kopylova G., Shchepkin D., Nabiev S., Matyushenko A.M., Levitsky D.I. Functional studies of tropomyosin mutations associatedwith dilated and hypertrophic cardiomyopathy. [49] Fatkhrakhmanova M.R., Mukhutdinova K.A., Kasimov M.R., Petrov A.M. The role of glutamate NMDA-receptor-NO synthase axis in the effectof 24-hydroxycholesterolon synaptic vesicle exocytosis at the mouseneuromuscular junctions. [50] Gritsyna Y., Vikhlyantsev I.M., Salmov N., Bobylev A.G., Podlubnaya Z.A. Increasing μ-calpain activity in striated muscles of alcohol-fed rats. [50] Kochubey P.V., Bershitsky S.Y. Study of biphasic tension rise in contracting muscle fiberduring ramp stretch. [51] Kopylova G., Shchepkin D., Nabiev S., Nikitina L., Bershitsky S.Y. The Ca2+ regulation of actin-myosin interactionin atrium and ventricle. [51] Nabiev S., Bershitsky S.Y., Tsaturyan A. Measurements of the bending stiffnessof reconstructed thin filament with the optical trap. [51] Shchepkin D., Kopylova G., Matyushenko A.M., Popruga K.E., Pivovarova A.V., Levitsky D.I. Structural and functional studies of tropomyosin species withcardiomyopathic mutations in the areaof tropomyosin-troponin contact. [52] Shenkman B., Nemirovskaya T.L., Lomonosova Y.N., Lyubimova K.A., Ptitsyn K.G. Nitric oxide in uloaded muscle: powerless guard of stability. [52] Shirinsky V.P., Kazakova O.A., Samsonov M.V., Khalisov M.M., Khapchaev A.Yu., Penniyaynen V.A., Ankudinov A.V., Krylov B.V.Spatiotemporal activity profiling of key myosin regulators inendothelial cells with regard to control of cell stiffnessand barrier dysfunction. [53] Yakupova E.I., Bobylev A.G., Vikhlyantsev I.M., Podlubnaya Z.A. Smooth muscle titin forms aggregates with amyloid-likedye-binding properties. [53] MEDICAL BIOINFORMATICS. [54] Eskov V.M., Khadartsev A.A., Gavrilenko T.V., Filatov M.A. Homeostasis and the evolution of complex biological systems. [54] Gorbunov D.V., Garaeva G.R., Sinenko D.V., Grigorenko V.V. Limit of applicability the theorem of Glansdorf-Prigoginein the describing homeostatic systems. [54] Iaparov B.Y., Moskvin A., Solovyova O.E. Electron-conformational transformations governthe temperature dependence of the RYR2 gating. [54] Lookin N. Towards to the bio-computer: from serial von Neumann architectureto systolic computer system in one chip. [55] Obesnyuk V.F. Hybrid technology of cohort rate of conditionallifetime risk trend assessment. [55] Parshin D.V., Cherevko A., Chupakhin A., Orlov K., Ufimtseva I., Krivoshapkin A. Analytical methods for diagnostics of cerebral aneurysms. [56] Rudenko E., Shchegolev B. Parathyroid hypertensive factor (PHF) - β2-adrenergic receptorpotential antagonist. [56] Ryvkin A.М., Moskvin A. Probabilistic theory of ions binding to RYR-channelwithin the improved electron-conformational model. [56] Shadrin K.V., Pakhomova V., Rupenko A. Stoichiometric modeling of oxygen transport through the surfaceof the isolated perfused rat liver at various oxygenation conditions. [57] Zubarev A.Y. Theoretical modelling of magnetic hyperthermia. [57] TRANSLATIONAL MEDICINE. FROM BASIC SCIENCE TO CLINICAL PRACTICE. [58] Blinkova N.B., Danilova I.G., Gette I.F., Abidov M.T., Pozdina V.A. Features of the regenerative processesin the rat liver exposed to alloxan diabetes with stimulationof macrophages functional activity. [58] Bulavintseva T.S., Danilova I.G., Brilliant S.A. The response of macrophage to chronic hyperglycemiabefore and after modulation of macrophage functional phenotype. [58] Chumarnaya T.V., Alueva Y.S., Kochmasheva V.V., Mikhailov S.P., Ostern O.V., Sopov O.V., Solovyova O.E. Specific features of the functional geometryof the left ventricle in myocardial diseases. [59] Kolobov A.V., Kuznetsov M.B., Simakov S., Gorodnova N. Multiscale modeling of angiogenic tumor growth and progression. [59] Maryakhina V.S., Ovechkin M.V., Spirina V.I. Laser flash photolysis in investigation of breast cancerat different stages of tumor development. [59] Nikitina E.A., Zhuravlev A.V., Zakharov G.A., Medvedeva A.V., Dolgaya Y.F., Ivanova P.N., Tokmacheva E.V., Savvateeva-Popova E.V. Genetic and epigenetic aspectsof neurodegenerative diseases etiopathogenesis. [60] Pichugova S.V., Komarova S.Y., Beykin Y.B. Electron microscopy in the diagnosis of male infertility. [60] Pyankova Z.A., Medvedeva S.Y., Gette I.F., Belousova A.V. Influence of the pericellular microenvironmentto the functional liver cells damaged by toxin. [61] Smirnyh S.E., Chereshneva M.V., Danilova I.G.The dynamics of the regenerative processes in the retina in rats withalloxan diabetes and after injectionof tetrahydrophthalazine derivatives. [61] Solodushkin S.; Stolyar A. Mathematical modelling of the kidney transplant outcomes. [62] Tsyvian P.B. Hemodynamics and regulation of angiogenesis in human embryoconceived by in vitro fertilization. [62] Zotova N. Methodological approaches to identificationof Systemic Inflammation under sepsis. [62] MEDICAL CHEMISTRY[64] Bozhko Y., Bakhtin V.M., Belokonova N.A. On correction and prevention of magnesium deficiency. [64] Chernaya L.V., Kovalchuk L.A., Nokhrina E.S., Nikonov G.I. Biological active trace elements of medicinal leeches Hirudomedicinalis L., 1758 and Hirudo verbana Carena, 1820, grown inartificial conditions of regional biofactories in Russia. [64] Emelianov V.V., Savateeva E.A., Sidorova L.P., Tseitler T.A., Gette I.F., Bulavintseva T.S., Smirnyh S.E., Danilova I.G., Maksimova N.E., Mochulskaya N.N., Chupakhin O.N., Chereshnev V.A. 1,3,4-thiadiazine derivates – antioxidants and protein glycationblockers – for correction of experimental diabetes mellitus. [65] Gagarin I., Tonkushina M.O., Ostroushko A.A., Grzhegorzhevskii K.V. Modelling of {Mo72Fe30} electrophoresis. [65] Kurgina T.A., Anarbaev R.O., Lavrik O.I. Poly(ADP-ribose)polymerase 1 is one of the targetsfor the anti-cancer drugs search. [66] Sapozhnikova I.M., Deeva E.G., Konovalova N.I. Synthesis and antiviral activity of nitrile-containing1,2,4-triazolo [5,1-c]-1,2,4-triazines. [66] Savateev K. New perspective series of adenosine receptors inhibitors. [66] Tarkhanova A.E., Kovalchuk L.A. The estimate of the concentrations of macroelements and traceelements in the biological system of obese pregnant women: (bloodof mother – placenta – blood of newborn babies). [67] Tonkushina M.O., Ostroushko A.A., Gagarin I. Associates of Mo72Fe30. [67] Trebukhov A.V., Shirmanova E.A., Trebuhov A.V. The study of the effects of L-arginine and taurine-contains drugs onplatelet aggregation performance and lipid metabolism in patientswith heart diseases. [68] Voinkov E. Nitroacetonitrile is the intermediatefor the synthesis of azolo-6-azapurines. [68] BIOMEDICAL TECHNOLOGY. [69] Balashov V.A., Agladze K.I., Agapov I.I., Efimov A.E. The study of cardiomyocyte structureby scanning probe nanotomography. [69] Chibireva M.D. Development of the way of early diagnosticof essential arterial hypertension different forms in adolescents. [69] Ivanov V.Y., Antsygin I.N., Sedunova I.Н., Myshkina A.V Training for biomedical engineering at the Ural Federal University. [70] Klyueva Y. CD45RA+ T-lymphocytes levels evaluation

Examination of myocardial electrophysiology using novel panoramic optical mapping techniques

Optical mapping of voltage signals has revolutionised the field and study of cardiac electrophysiology by providing the means to visualise changes in electrical activity at a high temporal and spatial resolution from the cellular to the whole heart level under both normal and disease conditions. The aim of this thesis was to develop a novel method of panoramic optical mapping using a single camera and to study myocardial electrophysiology in isolated Langendorff-perfused rabbit hearts. First, proper procedures for selection, filtering and analysis of the optical data recorded from the panoramic optical mapping system were established. This work was followed by extensive characterisation of the electrical activity across the epicardial surface of the preparation investigating time and heart dependent effects. In an initial study, features of epicardial electrophysiology were examined as the temperature of the heart was reduced below physiological values. This manoeuvre was chosen to mimic the temperatures experienced during various levels of hypothermia in vivo, a condition known to promote arrhythmias. The facility for panoramic optical mapping allowed the extent of changes in conduction timing and pattern of ventricular activation and repolarisation to be assessed. In the main experimental section, changes in epicardial electrical activity were assessed under various pacing conditions in both normal hearts and in a rabbit model of chronic MI. In these experiments, there was significant changes in the pattern of electrical activation corresponding with the changes in pacing regime. These experiments demonstrated a negative correlation between activation time and APD, which was not maintained during ventricular pacing. This suggests that activation pattern is not the sole determinant of action potential duration in intact hearts. Lastly, a realistic 3D computational model of the rabbit left ventricle was developed to simulate the passive and active mechanical properties of the heart. The aim of this model was to infer further information from the experimental optical mapping studies. In future, it would be feasible to gain insight into the electrical and mechanical performance of the heart by simulating experimental pacing conditions in the model

All-Optical 4D In Vivo Monitoring And Manipulation Of Zebrafish Cardiac Conduction

The cardiac conduction system is vital for the initiation and maintenance of the heartbeat. Over the recent years, the zebrafish (Danio rerio) has emerged as a promising model organism to study this specialized system. The embryonic zebrafish heart’s unique accessibility for light microscopy has put it in the focus of many cardiac researchers. However, imaging cardiac conduction in vivo remained a challenge. Typically, hearts had to be removed from the animal to make them accessible for fluorescent dyes and electrophysiology. Furthermore, no technique provided enough spatial and temporal resolution to study the importance of individual cells in the myocardial network. With the advent of light sheet microscopy, better camera technology, new fluorescent reporters and advanced image analysis tools, all-optical in vivo mapping of cardiac conduction is now within reach. In the course of this thesis, I developed new methods to image and manipulate cardiac conduction in 4D with cellular resolution in the unperturbed zebrafish heart. Using my newly developed methods, I could detect the first calcium sparks and reveal the onset of cardiac automaticity in the early heart tube. Furthermore, I could visualize the 4D cardiac conduction pattern in the embryonic heart and use it to study component-specific calcium transients. In addition, I could test the robustness of embryonic cardiac conduction under aggravated conditions, and found new evidence for the presence of an early ventricular pacemaker system. My results lay the foundation for novel, non-invasive in vivo studies of cardiac function and performance

Remodelling of the cardiac caveolar domain in heart failure and its putative influence on beta adrenergic signalling

Over 500,000 people in the UK have heart failure (HF). After an initial insult to the heart, sympathetic drive increases which leads to detrimental remodelling of cardiac β-adrenergic receptors (βAR) and further cardiac dysfunction. The main βAR expressed in the heart are the β1AR and β2AR. In heart failure, remodelling is characterised by reduced β1AR density, desensitisation of the remaining β1AR and aberrations of normal βAR signal compartmentalisation. Caveolae, flask-shaped lipid rafts, are present in most cells including cardiac myocytes and are characterised by the presence of caveolin and cavin proteins. Caveolar proteins create distinct micro-domains within the membrane and play a key role in compartmentalisation of signalling from both the β1AR and β2AR. Isolated reports of changes in caveolar structure and proteins in HF have implications for β-AR signalling, however the full array of caveolar protein changes in HF has not previously been assessed. Here we establish how the expression and membrane location of β-AR cascade and caveolar proteins changes in rat models of right ventricular (RV) and left ventricular (LV) failure induced by monocrotaline and aortic banding, respectively. For the RV model, we examined changes in β-AR responsiveness, and tested the potential for reversing functional and caveolar remodelling using a common LV therapy (the β-blocker metoprolol). Quantitative analyses of caveolar protein expression in myocyte and myocardial samples was also carried out using custom-designed calibrating peptides (CavCATs). Both HF models showed a reduction in caveolar protein expression, with protein redistribution also found in the RV model. Decreased expression of β-AR signalling proteins (β1AR, adenylyl cyclase) accompanied by increased expression of inhibitory proteins (Gαi, GRK2) was also observed in both models, with some remodelling of membrane distribution. β-blocker treatment in RV failure partially recovered expression of caveolar and β-AR cascade proteins. Cardiac β1AR responsiveness was reduced in RV failure and again, this was partially recovered by β-blocker treatment. Quantitative work highlights the importance of studying non muscle-specific caveolar protein isoforms in the cardiac myocyte given e.g. similar expression of Cav 3 and Cav 1 in these cells. Caveolae are dynamic membrane compartments which change in HF. This work suggests that caveolar changes affect β-AR signalling protein membrane location, which contributes to aberrations of signalling which (in the case of RV failure) can be reversed by β blockers