Biopacemaker acceleration without increased synchronization by chronic exposure to phorbol myristate acetate

L'activité électrique du coeur est initiée par la génération spontanée de potentiels d'action venant des cellules pacemaker du noeud sinusal (SN). Toute dysfonction au niveau de cette région entraîne une instabilité électrique du coeur. La majorité des patients souffrant d'un noeud sinusal déficient nécessitent l'implantation chirurgicale d'un pacemaker électronique; cependant, les limitations de cette approche incitent à la recherche d'une alternative thérapeutique. La base moléculaire des courants ioniques jouant un rôle crucial dans l'activité du noeud sinusal sont de plus en plus connues. Une composante importante de l'activité des cellules pacemakers semble être le canal HCN, responsable du courant pacemaker If. Le facteur T-box 3 (Tbx3), un facteur de transcription conservé durant le processus de l'évolution, est nécessaire au développement du système de conduction cardiaque. De précédentes études ont démontré que dans différentes lignées cellulaires le Phorbol 12-myristate 13-acetate (PMA) active l'expression du gène codant Tbx3 via des réactions en cascade partant de la protéine kinase C (PKC). L'objectif principal de cette étude est de tester si le PMA peut augmenter la fréquence et la synchronisation de l'activité spontanée du pacemaker biologique en culture. Plus précisément, nous avons étudié les effets de l'exposition chronique au PMA sur l'expression du facteur de transcription Tbx3, sur HCN4 et l'activité spontanée chez des monocouches de culture de myocytes ventriculaires de rats néonataux (MVRN). Nos résultats démontrent que le PMA augmente significativement le facteur transcription de Tbx3 et l'expression ARNm de HCN4, favorisant ainsi l'augmentation du rythme et de la stabilité de l'activité autonome. De plus, une diminution significative de la vitesse de conduction a été relevée et est attribuée à la diminution du couplage intercellulaire. La diminution de la vitesse de conduction pourrait expliquer l'effet négatif du PMA sur la synchronisation de l'activité autonome du pacemaker biologique. Ces résultats ont été confirmés par un modèle mathématique multicellulaire suggérant que des fréquences et résistances intercellulaires plus élevée pourraient induire une activité plus stable et moins synchrone. Cette étude amène de nouvelles connaissances très importantes destinées à la production d'un pacemaker biologique efficient et robuste.The normal heartbeat is initiated by the spontaneous generation of action potentials in pacemaker cells of the sinoatrial node (SAN) region. Dysfunction of this region leads to electrical instability of the heart. The majority of the patients with sinus node dysfunction require surgical implantation of electronic pacemaker devices; however, limitations of this therapeutic approach lead to a need to search for alternatives. To date, the molecular basis of the ionic currents which play pivotal role in SAN action potential has been discovered. It is thought that an important component of the pacemaker cells are HCN channels, responsible for the funny current (If) in the SAN. Meanwhile, T-box factor 3 known as an evolutionary conserved transcription factors is necessary for development of the conduction system. In previous studies, it has been shown that Phorbol 12-myristate 13-acetate (PMA) activates Tbx3 gene expression in a PKC-dependent manner in several cell lines. The main objective of this study is to test if PMA can increase the frequency and synchronization of spontaneous activity of cultured biopacemakers. More precisely, we studied the effects of chronic exposure to PMA on the expression of the Tbx3 transcription factor and HCN4 in neonatal rat ventricular myocytes monolayers and how spontaneous activity was altered. Our results show that PMA significantly increases the Tbx3 transcription factor and HCN4 mRNA expression favoring an increased in the rate and spatial-temporal stability of the spontaneous activity. In addition, a significant decrease in conduction velocity was found that is attributed to decrease electrical intercellular coupling of the cells. The decrease in the conduction velocity could explain the negative effect PMA has on synchronization of spontaneous activity of the biopacemaker. These findings are confirmed by a multicellular mathematical model implying that faster frequency and higher intercellular resistance of the pacemaker cells may lead to a more stable and less synchronous activity. This study provides important new knowledge to produce efficient and robust biological pacemakers

The electrophysiology of the atrioventricular node in normal and failing rabbit hearts

Conduction abnormalities affect prognosis in chronic heart failure (CHF). Previous investigators have observed abnormal delay in atrioventricular (AV) conduction in a rabbit model of left ventricular dysfunction (LVD) due to apical myocardial infarction. In this model, AV conduction time increased with increasing pacing rates, suggesting the most likely site of delay is the AV node. The mechanisms by which this occurs are not fully understood. The purpose of this thesis was to confirm that the abnormal prolongation of AV conduction time originates at the AV node in a rabbit model of LVD due to apical myocardial infarction, and explore possible mechanisms underlying the observation. Using surface electrogram recording and standardised pacing techniques in an isolated AV node tissue preparation I confirmed that there is abnormal prolongation of AV nodal conduction in this rabbit model of LVD, as evidenced by prolongation of atrio-hisian (AH) interval and Wenckebach cycle length (WCL) in LVD compared to control. Furthermore, using optical mapping of electrical activation using voltage sensitive dye I observed that the prolongation of the AH interval is predominantly a consequence of conduction delay between the inputs of the AV node and the compact nodal region. Neuro-hormonal derangement in chronic heart failure has a central role in the pathogenesis of the disease, with evidence of downregulation of beta ()-adrenoceptors in the left ventricular myocardium. I therefore explored the possibility of β-adrenoceptor downregulation in the AV node as a mechanism underlying the abnormal AH interval prolongation in LVD. There was no evidence of β-adrenoceptor downregulation in the AV node in LVD compared to control to account for the observed abnormal conduction delay. Adenosine is known to have profound effects on AV nodal conduction and the possibility of tonic excess of adenosine in LVD was explored as a possible mechanism for the prolonged conduction delay. Using an exogenously applied adenosine A1 receptor antagonist there was no evidence of excess endogenous adenosine in LVD compared to control. There was, however, an increase in the sensitivity of the LVD samples compared to control to exogenous adenosine, with a significant increase in AH interval and WCL with increasing concentrations. This thesis also investigates the effect of acidosis on AV nodal conduction. There was significant prolongation of the spontaneous sinus cycle length, AH interval and WCL, as well as the AV nodal functional and effective refractory periods, proportional to the degree of acidosis. These effects were reversible with return to normal pH. Optical mapping studies showed that the spatiotemporal pattern of AV nodal delay during acidosis was similar to that observed in LVD, with the predominant delay in conduction between the AV nodal inputs and the compact AV node. In summary this thesis has confirmed that even in the absence of a direct ischaemic insult to the AV junction, conduction abnormalities in the AV node may still occur as a pathophysiological response to a myocardial infarction resulting in LVD. The mechanisms underlying this response are likely to be complex and multiple, and are not yet clear. Establishing the electrophysiological basis and the effects of neuro-hormonal modulators of atrioventricular nodal function may lead to development of targeted therapeutic strategies to improve overall survival and improve symptom control for patients with CHF

Computational Analysis of Complex Beat-to-Beat Dynamics in Heart Cells

Contrary to the popular belief that the heart maintains a regular rhythm, healthy heartbeats fluctuate in a chaotic way. We now know that the fluctuations do not display uncorrelated randomness, but they contain long-range correlations and can be characterized by a fractal. This behavior supports the adaptability of the heart and may thus protect it from external stress. The fractal complexity is also found in the smallest parts of the heart: the cells. In the dawn of advanced pluripotent stem cell technology, producing independently beating cardiomyocytes in a laboratory, the beat-rate fluctuations of heart cells can be directly studied. In this thesis, we investigate the complex fluctuations in the field potentials generated by clusters of human cardiomyocytes. We show that the heart cells exhibit similar correlation properties in the beat-to-beat intervals and field potential durations comparable to RR and QT intervals, i.e., time between consecutive R waves and time from Q wave to the end of T wave, respectively, in an electrocardiogram of a heart. The cells are studied under conditions resembling real-life situations such as cardiac disorders, application of cardioactive drugs, and injuries. The results show significant alteration of the scaling properties in the beat rates, reflecting the changes in the intrinsic mechanism at the cellular level. By employing a set of nonlinear time series analysis tools, we explore their powerful applicability as well as their limitations. Our main method of choice throughout the work is detrended fluctuation analysis, which is designed to detect the degree of correlation in nonstationary time series. We demonstrate that detrended fluctuation analysis and its extensions are extremely useful in dealing with the field potential data of the heart cells despite the presence of abnormalities and irregular trends. The study of heartbeat dynamics at the cellular level using computational methods has important advantages. In particular, the methods provide non-invasive and versatile ways to improve our understanding of the intrinsic firing patterns of the heart cells, which play a crucial role in the future applications of in vitro human cardiomyocytes

Understanding altered intrinsic heart rate in type 2 diabetes

Heart rate (HR) is generated by sinoatrial node (SAN) intrinsic pacemaking and modulated by autonomic innervation. Within the SAN, intrinsic (ex vivo) HR is determined by the mutual entrainment of the sarcolemmal voltage membrane (Vm) and intracellular Ca2+ clocks. The Vm clock involves membrane ion channels, such as the hyperpolarisation-activated cyclic nucleotide-gated channel 4 (HCN4), transient type (T-type) and long-lasting type (L-type) Ca2+ channels and the ion transporter Na+-Ca2+ exchanger 1 (NCX1). The Ca2+ clock primarily involves the intracellular Ca2+ store, the sarcoplasmic reticulum (SR), and the Ca2+ release protein the ryanodine receptor 2 (RyR2), the Ca2+ uptake protein the sarco(endo)plasmic reticulum Ca2+-ATPase (SERCA2a) and its regulator phospholamban. Conduction of the AP within the SAN occurs via the coupling protein connexin 45 (cx45). Additionally, the presence of the non-neuronal cardiac intrinsic cholinergic system within cardiomyocytes suggests it might also be present in the SAN cardiomyocytes and have the capacity to modulate intrinsic HR. Disruption of HR control occurs in patients and animal models with type 2 diabetes (DM). Interestingly, in the DM Zucker Diabetic Fatty (ZDF) rats, intrinsic HR was significantly decreased compared to non-diabetic (nDM) controls. This suggests DM impairs the intrinsic ability of the SAN to generate a normal HR. Therefore, the overall aim of this research was to investigate whether the decreased intrinsic HR in DM was due to changes in the Vm and / or Ca2+ clocks, cx45 and / or increased non-neuronal intrinsic cholinergic system activity. The SAN / hearts of 19 – 22 week-old nDM and DM ZDF rats were used to investigate protein expression of the key SAN clock, cx45 and cholinergic proteins via western blotting, intrinsic HR contributions from HCN4, SERCA2a and muscarinic type 2 (M2) receptor via Langendorff, and SAN cellular / tissue morphology via immunohistochemistry. For the Vm clock, a significant increase in HCN4 (nDM 0.83 ± 0.07 versus DM 1.67 ± 0.19, p0.05) or SERCA2a to phospholamban ratio (nDM 2.97 ± 0.68 versus DM 2.37 ± 0.34, p>0.05) was found in DM. A significant increase in the M2 receptor expression (nDM 1.14 ± 0.18 versus DM 3.14 ± 0.80, p0.05). For immunohistochemistry, no difference in cellular / tissue distribution of key SAN clock, cx45 or cholinergic proteins was observed, or in the levels of fibrosis (p>0.05) and fat (p>0.05) within the DM SAN. Collectively, this study presents novel mechanisms that are altered in pacemaking in the type 2 DM SAN. From this research, I conclude, the lower intrinsic HR in DM is, in part, a result of changes to both the Vm and Ca2+ clock due to non-functional HCN4 channels and compromised SERCA2a activity that would prolong diastolic depolarisation and repolarisation respectively

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. 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Spiral-wave dynamics in a mathematical model of human ventricular tissue with myocytes and fibroblasts

Cardiac fibroblasts, when coupled functionally with myocytes, can modulate the electrophysiological properties of cardiac tissue. We present systematic numerical studies of such modulation of electrophysiological properties in mathematical models for (a) single myocyte-fibroblast (MF) units and (b) two-dimensional (2D) arrays of such units; our models build on earlier ones and allow for zero-, one-, and two-sided MF couplings. Our studies of MF units elucidate the dependence of the action-potential (AP) morphology on parameters such as , the fibroblast resting-membrane potential, the fibroblast conductance , and the MF gap-junctional coupling . Furthermore, we find that our MF composite can show autorhythmic and oscillatory behaviors in addition to an excitable response. Our 2D studies use (a) both homogeneous and inhomogeneous distributions of fibroblasts, (b) various ranges for parameters such as , and , and (c) intercellular couplings that can be zero-sided, one-sided, and two-sided connections of fibroblasts with myocytes. We show, in particular, that the plane-wave conduction velocity decreases as a function of , for zero-sided and one-sided couplings; however, for two-sided coupling, decreases initially and then increases as a function of , and, eventually, we observe that conduction failure occurs for low values of . In our homogeneous studies, we find that the rotation speed and stability of a spiral wave can be controlled either by controlling or . Our studies with fibroblast inhomogeneities show that a spiral wave can get anchored to a local fibroblast inhomogeneity. We also study the efficacy of a low-amplitude control scheme, which has been suggested for the control of spiral-wave turbulence in mathematical models for cardiac tissue, in our MF model both with and without heterogeneities

Model-based Analysis of Temporal Patterns in Atrioventricular Node Conduction During Atrial Fibrillation

The lifetime risk of developing atrial fibrillation (AF) is estimated to be between 1in 3 to 1 in 4 individuals, making it the most common arrhythmia in the world.For persistent AF, rate control drugs with the purpose to affect the conduction properties of the atrioventricular (AV) node are the most common treatment. The drug of choice varies between β-blockers and calcium channel blockers, often chosen empirically. This can lead to long periods of time before sufficient treatment is found. However, due to the physiological differences between the drug types, it could be possible to predict the effect of the drugs and thus assist in treatment selection. The main focus of this thesis is therefore to assess drug-dependent differences in the AV node, using non-invasive measurements. This thesis comprises an introduction to the subject as well as two papers. The first paper proposes a framework for assessing the conduction properties of the AV node non-invasively using a mathematical model of the AV node in combination with a genetic algorithm.The second paper is a continuation of the work in paper I, where the proposed workflow was adapted to assess the drug-dependent effect on the AV node of four different rate control drugs during a period of 24 hours.The methods presented in this thesis have made it possible to assess both the refractory period and the conduction delay in the AV node in a robust way using ECG, and by doing so found population-related differences in AV node conduction properties between drug types