cardiac arrhythmia; fibrosis; myofibroblast; arrhythmia mechanisms; cardiomyocyte; optical recording; stroma-parenchyme interaction; impulse conduction; ectopic activity
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.
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.
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.
Jousset Florian, Rohr Stephan (2015), Optical recording of calcium currents during impulse conduction in cardiac tissue, in Neurophotonics
, 2(2), 1-9.
Grand Teddy, Salvarani Nicolò, Jousset Florian, Rohr Stephan (2014), Aggravation of cardiac myofibroblast arrhythmogeneicity by mechanical stress, in Cardiovascular Research
, 104(3), 489-500.
Grand T Salvarani N Jousset F Rohr S (2014), Aggravation of cardiac myofibroblast arrhythmogenicity by mechanical stress., in Cardiovascular Research
, 104(3), 489-500.
Rohr Stephan (2012), Arrhythmogenic implications of fibroblast-myocyte interactions, in Circulation: Arrhythmia and Electrophysiology
, 5(2), 442-452.
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.
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.
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.
Rohr Stephan (2011), Cardiac fibroblasts in cell culture systems: Myofibroblasts all along?, in Journal of Cardiovascular Pharmacology
, 57(4), 389-399.
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.