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Structural and Electrical Remodeling of Cardiac Tissue: Consequences for Impulse Generation and Propagation at the Cellular Network Level.

English title Structural and Electrical Remodeling of Cardiac Tissue: Consequences for Impulse Generation and Propagation at the Cellular Network Level.
Applicant Rohr Stephan
Number 138297
Funding scheme Project funding (Div. I-III)
Research institution Institut für Physiologie Medizinische Fakultät Universität Bern
Institution of higher education University of Berne - BE
Main discipline Cardiovascular Research
Start/End 01.10.2011 - 30.09.2015
Approved amount 398'000.00
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All Disciplines (2)

Discipline
Cardiovascular Research
Pathophysiology

Keywords (9)

cardiac arrhythmia; fibrosis; myofibroblast; arrhythmia mechanisms; cardiomyocyte; optical recording; stroma-parenchyme interaction; impulse conduction; ectopic activity

Lay Summary (German)

Lead
Lay summary

Bluthochdruck, Herzinfarkt, fortgeschrittenes Alter und genetische Veranlagung führen zu krankhaften Veränderungen der Herzmuskelstruktur (‘Strukturelles Remodeling’), welche die normale Pumpfunktion des Organs beeinträchtigen und Herzrhythmusstörungen induzieren. Typischerweise sind diese strukturellen Veränderungen vom Auftreten sogenannter Myofibroblasten im Herzmuskelgewebe begleitet. Dieser spezielle Bindegewebszelltyp zeichnet sich durch eine übermässige Produktion von Bindegewebsfasern aus, welche die Pumpfunktion des Herzmuskels einschränken und dessen elektrische Erregung beeinträchtigen.

Vor einigen Jahren gelang es uns erstmals zu zeigen, dass Myofibroblasten auch dazu befähigt sind, in Zellkultur elektrischen Kontakt mit Herzmuskelzellen aufzunehmen. Diese Kontaktaufnahme basiert auf der Ausbildung elektrisch leitender Kanälen zwischen Myofibroblasten und Herzmuskelzellen aufgrund derer Myofibroblasten beispielsweise die elektrische Kontinuität zwischen durchtrennten Herzmuskelgeweben wiederherstellen können. Dies trägt möglicherweise zur Erklärung bei, weshalb es nach Herztransplantationen zur elektrischen Synchronisation zwischen Spender- und Empfängergewebe kommen kann. Während dies als positiv gewertet werden kann, fanden wir auch höchst nachteilige Konsequenzen der elektrischen Kopplung zwischen Herzmuskelzellen und Myofibroblasten. Insbesondere beobachteten wir eine pathologische Verlangsamung der Ausbreitung der Herzmuskelerregung sowie die Entstehung spontaner elektrischer Aktivierungen. Beide pathologischen Zustände konnten auf eine Myofibroblasten-induzierte Verringerung der elektrischen Polarisierung der Herzmuskelzellen zurückgeführt werden. Wie zu erwarten war, führte die Kombination dieser funktionellen Störungen zum Entstehen kreisender Erregungen, welche als Hauptursache des plötzlichen Herztodes gelten. Unsere Untersuchungen weisen entsprechend darauf hin, dass Herzrhythmusstörungen nicht nur, wie bisher angenommen, auf Probleme der elektrischen Eigenschaften von Herzmuskelzellverbänden zurückzuführen sind,  sondern dass auch Myofibroblasten möglicherweise eine zentrale Rolle spielen.

Entsprechend dieser Hypothese ist es das Ziel vorliegender Studie, die mögliche Rolle der Myofibroblasten bei der Entstehung von Herzrhythmusstörungen weiter im Detail zu charakterisieren. Dabei steht die Beantwortung folgender Fragen im Zentrum: (1) Ist die von uns in-vitro beobachtete elektrische Kopplung zwischen Myofibroblasten und Herzmuskelzellen auch im strukturell veränderten intakten Herzmuskelgewebe nachweisebar? (2) Welche Ionenkanäle bestimmen die elektrischen Eigenschaften von Myofibroblasten und sind damit mitverantwortlich für deren arrhythmogene Wirkung auf die Herzmuskelzellen? (3) Wie entwickelt sich die arrhythmogene Interaktion zwischen Myofibroblasten und Herzmuskelzellen im Verlauf der Zeit (transientes oder stabiles Phänomen; Beobachtung mittels neuem experimentellem Ansatz)? (4) Inwiefern wird die Etablierung stabiler elektrischer Verbindungen zwischen Herzmuskelzellen und Myofibroblasten vom Migrationsverhalten letzterer beeinflusst?

Falls mittels dieser Studie die Annahme gefestigt werden kann, dass Myofibroblasten bei der Entstehung von Herzrhythmusstörungen ursächlich beteiligt sind, stellt dies nicht nur einen neuen Erklärungsansatz für diese allzu häufig fatal endende Erkrankung dar, sondern es ergäben sich auch neue spezifische Ansätze zur Behandlung dieser ausserordentlich häufigen Störung der Herzfunktion.


Direct link to Lay Summary Last update: 21.02.2013

Responsible applicant and co-applicants

Employees

Publications

Publication
Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model
Florian Jousset Ange Maguy Stephan Rohr† and Jan P. Kucera*† (2016), Myofibroblasts Electrotonically Coupled to Cardiomyocytes Alter Conduction: Insights at the Cellular Level from a Detailed In silico Tissue Structure Model, in Frontiers in Physiology, 7(496), 1-23.
Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo.
D. Brönnimann T. Djukic R. Triet C. Dellenbach I. Saveljic M. Rieger S. Rohr N. Filipovic V. (2016), Pharmacological Modulation of Hemodynamics in Adult Zebrafish In Vivo., in PLoS ONE , 11(3), 1-11.
PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers.
F. Syeda A.P. Holmes T.Y. Yu S. Tull S.M. Kuhlmann D. Pavlovic D. Betney G. Riley J.P. Kucer (2016), PITX2 Modulates Atrial Membrane Potential and the Antiarrhythmic Effects of Sodium-Channel Blockers., in Journal of the American College of Cardiology, 68(17), 1881-1894.
Optical recording of calcium currents during impulse conduction in cardiac tissue
Jousset Florian, Rohr Stephan (2015), Optical recording of calcium currents during impulse conduction in cardiac tissue, in Neurophotonics, 2(2), 1-9.
Aggravation of cardiac myofibroblast arrhythmogeneicity by mechanical stress
Grand Teddy, Salvarani Nicolò, Jousset Florian, Rohr Stephan (2014), Aggravation of cardiac myofibroblast arrhythmogeneicity by mechanical stress, in Cardiovascular Research, 104(3), 489-500.
Aggravation of cardiac myofibroblast arrhythmogenicity by mechanical stress.
Grand T Salvarani N Jousset F Rohr S (2014), Aggravation of cardiac myofibroblast arrhythmogenicity by mechanical stress., in Cardiovascular Research, 104(3), 489-500.
Arrhythmogenic implications of fibroblast-myocyte interactions
Rohr Stephan (2012), Arrhythmogenic implications of fibroblast-myocyte interactions, in Circulation: Arrhythmia and Electrophysiology, 5(2), 442-452.
The natural cardioprotective particle HDL modulates connexin43 gap junction channels
Morel Sandrine, Morel Sandrine, Frias Miguel A., Rosker Christian, James Richard W., Rohr Stephan, Kwak Brenda R., Kwak Brenda R. (2012), The natural cardioprotective particle HDL modulates connexin43 gap junction channels, in Cardiovascular Research, 93(1), 41-49.
A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart
Miragoli Michele, Sheikh Abdul Kadir Siti H., Sheppard Mary N., Salvarani Nicoló, Virta Matilda, Wells Sarah, Lab Max J., Nikolaev Viacheslav O., Moshkov Alexey, Hague William M., Rohr Stephan, Williamson Catherine, Gorelik Julia (2011), A protective antiarrhythmic role of ursodeoxycholic acid in an in vitro rat model of the cholestatic fetal heart, in Hepatology, 54(4), 1282-1292.
Abolishing Myofibroblast Arrhythmogeneicity by Pharmacological Ablation of alpha-Smooth Muscle Actin Containing Stress Fibers
Rosker Christian, Salvarani Nicolo, Schmutz Stephan, Grand Teddy, Rohr Stephan (2011), Abolishing Myofibroblast Arrhythmogeneicity by Pharmacological Ablation of alpha-Smooth Muscle Actin Containing Stress Fibers, in CIRCULATION RESEARCH, 109(10), 1120-1131.
Cardiac fibroblasts in cell culture systems: Myofibroblasts all along?
Rohr Stephan (2011), Cardiac fibroblasts in cell culture systems: Myofibroblasts all along?, in Journal of Cardiovascular Pharmacology, 57(4), 389-399.

Collaboration

Group / person Country
Types of collaboration
FP-7 EUTRAF Great Britain and Northern Ireland (Europe)
- in-depth/constructive exchanges on approaches, methods or results
- Publication
Fondation Leducq United States of America (North America)
- in-depth/constructive exchanges on approaches, methods or results

Scientific events

Active participation

Title Type of contribution Title of article or contribution Date Place Persons involved
Cardiovascular and Metabolic Research Conference Poster Optical Recording of Calcium Currents during Impulse Propagation in Cardiac Tissue 22.01.2015 Fribourg, Switzerland Rohr Stephan;
38th Meeting of the European Working Group on Cardiac Cellular Electrophysiology Poster Altered ion currents, cell-to-cell variability of the Na+ current and of cell capacitance and heterocellular interactions cooperate in remodeling the action potential in dilated atria during heart failure 20.09.2014 Maastricht, Netherlands Rohr Stephan;
Cardiostim 2014- 19th World Congress in Electrophysiology & Cardiac Techniques Poster Cell-To-Cell Variability of Na+ Current Density and Cell Capacitance Contributes to the Variability of the Rate of Rise and the Amplitude of the Action Potential during Propagation in Atrial Tissue 18.06.2014 Nice, France Rohr Stephan;
Cardiac Arrhythmia Meeting Copenhagen Talk given at a conference Cardiac Fibroblasts 19.05.2014 Copenhagen, Denmark Rohr Stephan;
Cardiovascular and Metabolic Research Conference Poster Cell-to-cell variability of Na+ current density and of cell capacitance contributes to the variability of the rate of rise and the amplitude of the action potential during impulse propagation in atrial tissue 17.01.2014 Fribourg, Switzerland Rohr Stephan;
Annual Meeting of the Swiss Physiological Society Talk given at a conference Controlling myofibroblast arrhythmogeneicity with optogenetic tools 10.09.2013 Bern, Switzerland Rohr Stephan;
LDDR congress: Local Drug Delivery Meeting and Cardiovascular and Molecular Strategies Poster Growth Factors Increase Gap Junctional Coupling in Hybrid Cardiomyocyte-Myofibroblast Cell Pairs 07.02.2013 Geneva, Switzerland Salvarani Nicolo; Rohr Stephan;
Biophysical Society Meeting Poster Changes of axial resistance following mechanical strain prevail over stretch-activated currens in the moudlation of conduciton velocity in cardiac cell strands 02.02.2013 Philadelphia, United States of America Rohr Stephan;
Cardiovascular and Metabolic Research Conference Talk given at a conference Activated fibroblasts in the heart: More than passive bystanders in cardiac arrhythmogenesis? 11.01.2013 Bern, Switzerland Rohr Stephan;
Cardiovascular and Metabolic Research Conference Poster How does stretch of cardiac tissue influence the velocity of action potential propagation? Insights from experiments and computer simulations. 10.01.2013 Bern, Switzerland Rohr Stephan;
American Heart Association Scientific Sessions 2012 Talk given at a conference Growth Factors Increase Gap Junctional Coupling in Hybrid Cardiomyocyte-Myofibroblast Cell Pairs 03.11.2012 Los Angeles, United States of America Rohr Stephan; Salvarani Nicolo;
American Heart Association Scientific Sessions 2012 Talk given at a conference Aggravation of Myofibroblast Arrhythmogeneicity by Mechanical Stress. 03.11.2012 Los Angeles, United States of America Rohr Stephan;
American Heart Association Scientific Sessions 2012 Talk given at a conference Optogenetic Control of Arrhythmogenic Myofibroblast-Cardiomyocyte Interactions 03.11.2012 Los Angeles, United States of America Rohr Stephan;
Cardiostim 2012 - 18th World Congress in Electrophysiology & Cardiac Techniques Talk given at a conference Myofibroblasts as arrhythmia triggers 13.06.2012 Nice, France Rohr Stephan;
Molecular Cardiology Seminar of the AMC Individual talk Cardiac myofibroblasts in arrhythmogenesis: Concepts and future directions. 12.04.2012 Amsterdam, Netherlands Rohr Stephan;


Knowledge transfer events

Active participation

Title Type of contribution Date Place Persons involved
Nacht der Forschung Performances, exhibitions (e.g. for education institutions) 23.10.2011 Bern, Switzerland Salvarani Nicolo; Rohr Stephan;


Self-organised

Title Date Place
Tag der offenen Tür, Institut für Physiologie 30.06.2012 Bern, Switzerland

Associated projects

Number Title Start Funding scheme
118247 Structural and electrical remodeling of cardiac tissue: Consequences for impulse generation and propagation at the cellular network level 01.10.2007 Project funding (Div. I-III)
150823 Serial block face SEM 01.12.2013 R'EQUIP
169234 Structural and Functional Evidence for Electrotonic Coupling Between Stromal and Parenchymal Cells in the Heart 01.11.2016 Project funding (Div. I-III)
169234 Structural and Functional Evidence for Electrotonic Coupling Between Stromal and Parenchymal Cells in the Heart 01.11.2016 Project funding (Div. I-III)

Abstract

Cardiovascular diseases represent a substantial socio-economic burden for the industrialized world that is bound to increase over the next years as life expectancy rises. The main manifestation of cardiac disease, i.e., compromised pump function and arrhythmias, most often occur on the background of structurally remodeled fibrotic myocardia. Whereas fibrosis is arrhythmogenic per se by disrupting the normally uniform electrical substrate for impulse conduction, we found recently that a specific cell population typically appearing in fibrosis, the myofibroblasts, directly contribute to arrhythmogenesis following establishment of heterocellular communication with cardiomyocytes by providing depolarizing ‘injury current’ flow to the latter. Within the framework of the present proposal, we intend to further characterize this concept by addressing the following questions: (1) Temporal evolution and long-term stability of arrhythmogenic interactions between myofibroblasts and cardiomyocytes. Until now, neither the initial evolution nor the long-term stability of arrhythmogenic interactions between myofibroblasts and cardiomyocytes has been characterized in the temporal domain due to a lack of appropriate experimental approaches. In order to address this issue important for a comprehensive characterization of myofibroblast arrhythmogeneicity, we propose to develop a dedicated recording system that will permit the assessment of functional and structural aspects of electrotonic myofibroblast-cardiomyocyte interactions over time and, furthermore, supports efficient screening of interventions aimed at modifying these arrhythmogenic interactions.(2) Characterization of the ion channel repertoire of myofibroblasts. The identification of ion channels underlying the moderate polarization of myofibroblasts and the biophysical characterization of gap junctional conductances of myofibroblast-cardiomyocytes pairs is prerequisite for a comprehensive understanding of arrhythmogenic current flow from myofibroblasts to cardiomyocytes. Accordingly, we will conduct a systematic characterization of these determinants of myofibroblast arrhythmogeneicity with the goal to identify possible targets for antiarrhythmic therapies. (3) Cell motility and the formation of stable heterocellular gap junctional coupling. Both myofibroblasts and fibroblasts are migratory cells, which questions their ability to establish lasting functional gap junctional coupling with cardiomyocytes. This apparent contradiction to the previously observed stable electrotonic interaction with cardiomyocytes will be investigated by assessing the dynamics of the molecular makeup of myofibroblast-cardiomyocyte adhesion junctions over time with the goal to test the hypothesis that fibroblasts might be less likely to establish heterocellular gap junctions than myofibroblasts based on their inherently faster migration.(4) Myofibroblast-cardiomyocyte coupling in intact cardiac tissue, fact or fiction? The extrapolation of previous findings of arrhythmogenic effects of myofibroblasts on cardiomyocytes in-vitro to diseased hearts in-vivo awaits proof of heterocellular coupling between both cell types in intact cardiac tissue. Using a two-photon microscopy approach, we intend to find evidence for presence (or absence) of functional gap junctional coupling between the two cell types in diseased myocardium. If such coupling should exist, myofibroblasts might emerge as a novel non-cardiomyocyte target for antiarrhythmic therapy.Overall, the projects proposed are expected to advance our understanding of the biophysical mechanisms underlying myofibroblast arrhythmogeneicity at the molecular, cellular and tissue level with the ultimate goal to arrive at a comprehensive understanding of the role of myofibroblasts in arrhythmias of the structurally remodeled heart.
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