Editorial
Follow the white rabbit*: Experimental and computational models of the rabbit heart provide insights into cardiac (patho-) physiology
*Lewis Carrol, Alice in Wonderland
Katja E. Odening1,2,3 MD; Peter Kohl2,3,4 MD PhD
1Department of Cardiology and Angiology I, University Heart Center Freiburg – Bad Krozingen, Medical Center – University of Freiburg, Germany;
2Institute for Experimental Cardiovascular Medicine, University Heart Center Freiburg– Bad Krozingen, Medical Center – University of Freiburg, Germany
3Faculty of Medicine, University of Freiburg, Germany
4Cardiac Biophysics and Systems Biology, National Heart and Lung Institute, London, UK
Basic research to improve our understanding of the complex, multi-dimensionalregulatory processes governing physiological and pathological cardiac function–particularlyif combined with the goal of ‘bench to bedside’ translation–requires animal models that capture essential aspects of human physiology. The rabbit – the largest of the small laboratory animals –represents a species that mimics human cardiac (patho-) physiology surprisingly well: The‘relative size’of electrophysiological and structural characteristics of the rabbit heart closely resemble those of human (Panfilov, 2006).Rabbit coronary architecture and responses to ischemia are fairly similar to human (Harken et al., 1981; Galinanes and Hearse, 1990). Key electrical features show pronounced similarities in the two species, in terms of ion currents determining cardiac action potential properties, intracellular ion concentrations, and responses to electrophysiologically relevant pharmacological interventions(Nerbonne, 2000;Valentin et al., 2004, Hondeghem et al., 2016).Regional contractile and diastolic behaviour of rabbit hearts resembles that of human(Jung et al. 2012), similar cardiac mechano-electrical coupling mechanisms have been described (Quinn et al., 2014), and both species express predominantly -myosin heavy chain (while mouse myocardium, for example, contains nearly exclusively -myosin heavy chain (Marian 2005)). Thanks to novel developments in animal transgenesis, rabbitshave entered the range of species in whom genetic manipulation can successfully replicate certain human cardiac diseases (Sanbe et al., 2005; Brunner et al., 2008; Odening et al., 2010; Major et al., 2016). Also, the rabbit heart has been among those that have been characterized on multiple levels from isolated cardiomyocyte, tissue culture, living cardiac tissue slices, to Langendorff-perfused hearts (Wang et al., 2014) and have been structurally and functionally imaged and computationally modelled in great detail (Burton et al., 2014;Lamata et al., 2014; Hooks et al., 2001; Li et al., 2004).
In this special issue of Progress in Biophysics and Molecular Biology,weprovide a snapshot of experimental and computational models of the rabbit heart used for cardiovascular research. Reviews and original papers cover themes from cardiac structure, to electrical and mechanical cardiac function, including novel insight from transgenic rabbit models– highlighting important insights from ion channel function to integrated behaviour, covering themes from arteriosclerosis to arrhythmogenesis.
Starting with technologies used for three-dimensional (3D) reconstruction from nano- to macro-scales, this issue provides an introduction to benefits and limitations of electron-microscopic tomography and its use for analysis of 3D ultra-structure of T-tubuliin rabbit cardiomyocytes (Rog-Zielinska et al., 2016). This is followed by an exploration of myocardial meso-structure, using diffusion-tensor imaging of whole rabbit hearts in different deformations states (Teh et al., 2016). Kang et al. (2016) then provide an overview of technical advances in the use of fluorescent imaging andstretchable electronics to study cardiac electrophysiology and mechanisms of arrhythmogenesis. The fourth in this set of papers explores the utility of rabbit hearts in cardiac mechano-electric and mechano-mechanical coupling research(Quinn and Kohl, 2016).
Novel genetic techniques for the generation of transgenic rabbit models that mimic human heart diseases are reviewed by Bosze et al. (2016), followed by articles that apply such models. Baumgartner et al. (2016) summarize past and current work on genetic and induced atherosclerosis in rabbit. Lang et al. (2016) present transgenic rabbit models of long QT syndrome and highlight the importance of regional heterogeneities in electrical and mechanical dysfunctionof the heart.Baczkó et al. (2016) illustrate the importance of normal and genetically-modified rabbit models for preclinical cardiac electrophysiological safety testing.
These articles on ‘wet’ experimental studies are followed by papers highlighting the utility of ‘dry’ rabbit-specific computational models in arrhythmia research. Gemmell et al. (2016) used populations of rabbit-specific computational cardiomyocyte models to reproduce more faithfully the electrophysiological variability in responses to ischemia. Arevalo et al. (2016) illustrate the utility of computational rabbit models to investigate initiation, perpetuation, and termination of ventricular arrhythmias.
Of course, this special issue represents an excerpt only of the various applications of rabbit models in cardiovascular research. It illustrates, though, that non-murine models have a range of potentially important advantages, if particular for cardiovascular research. The editors hope that this collection of papers will stimulate interest and further research that ‘follows the white rabbit’ on a path to discovery.
Acknowledgement
We are indebted to Ms.PiaStroeger for excellent management preparations for this special issue. We are also most grateful to all our external reviewersfor their critical and constructive assessment that helped to improvethe quality of the focused issue. The editors acknowledge financial support by Deutsche Forschungsgemeinschaft, European ResearchCouncil, British Heart Foundation, and Deutsche StiftungfürHerzforschung.
Literature
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Wang, K., Terrar, D., Gavaghan, D.J., Mu-U-Min, R., Kohl, P., Bollensdorff, C., 2014; Living cardiac tissue slices: an organotypic pseudo two-dimensional model for cardiac biophysics research. ProgBiophys Mol Biol 2014;115(2-3):314-27
Lamata, P., Casero, R., Carapella, V., Niederer, S.A., Bishop, M.J., Schneider, J.E., Kohl, P., Grau, V., 2014;Images as drivers of progress in cardiac computational modelling.ProgBiophys Mol Biol 2014;115(2-3):198-212. Brunner, M., Peng, X., Liu, G.X., Ren, X.Q., Ziv, O., Choi, B.R., Mathur, R., Hajjiri, M., Odening, K.E., Steinberg, E., Folco, E.J., Pringa, E., Centracchio, J., Macharzina, R.R., Donahay, T., Schofield, L., Rana, N., Kirk, M., Mitchell, G.F., Poppas, A., Zehender, M., Koren, G., 2008; Mechanisms of cardiac arrhythmias and sudden death in transgenic rabbits with long QT syndrome.J Clin Invest 2008;118(6):2246-59.
Odening, K.E., Kirk, M., Brunner, M., Ziv, O., Lorvidhaya, P., Liu, G.X., Schofield, L., Chaves, L., Peng, X., Zehender, M., Choi, B.R., Koren, G., 2010; Electrophysiological studies of transgenic long QT type 1 and type 2 rabbits reveal genotype-specific differences in ventricular refractoriness and His conduction.Am J Physiol Heart Circ Physiol 2010;299(3):H643-55.
Major, P., Baczkó, I., Hiripi, L., Odening, K.E., Juhász, V., Kohajda, Z., Horváth, A., Seprényi, G., Kovács, M., Virág, L., Jost, N., Prorok, J., Ördög, B., Doleschall, Z., Nattel, S., Varró, A., Bősze, Z., 2016; A novel transgenic rabbit model with reduced repolarization reserve: long QT syndrome caused by a dominant-negative mutation of KCNE1 gene.Br J Pharmacol 2016 Apr 14. [Epub ahead of print]
Burton, R.A., Lee, P., Casero, R., Garny, A., Siedlecka, U., Schneider, J.E., Kohl, P., Grau, V., 2014; Three-dimensional histology: tools and application to quantitative assessment of cell-type distribution in rabbit heart.Europace 2014;16 Suppl 4:iv86-iv95.
Hooks, D.A., LeGrice, I.J., Harvey, J.D., Smaill, B.H., 2001;Intramural multisite recording of transmembrane potential in the heart.Biophys J 2001 Nov;81(5):2671-80.
Li, W., Kohl, P., Trayanova, N., 2004;Induction of ventricular arrhythmias following mechanical impact: a simulation study in 3D.J Mol Histol 2004;35(7):679-86.
Rog-Zielinska, E.A, Johnston, C.A., O'Toole, E.T., Morphew, M., Hoenger, A.,Kohl, P., 2016; Electron tomography of rabbit cardiomyocyte three-dimensional ultrastructure. ProgBiophys Mol Biol 2016, in press, this issue
Teh, I., Burton, R.A.B., McClymont, D., Capel, R.A., Aston, D., Kohl, P., Schneider, J.E., 2016.Mapping Cardiac Microstructure of Rabbit Heart in Different Mechanical States by High Resolution Diffusion Tensor Imaging. ProgBiophys Mol Biol 2016, in press, this issue
Kang, C., Brennan, J.A., Kuzmiak-Glancy, S., Garrott, K.E., Kay, M.W., Efimov, I.R., 2016. Technical advances in studying cardiac electrophysiology - role of rabbit models. ProgBiophys Mol Biol 2016, in press, this issue
Quinn, T.A. and Kohl, P., 2016; Rabbit as a model for studies of cardiac mechano-electric and mechano-mechanical coupling. ProgBiophys Mol Biol 2016, in press, this issue
Bosze, Z., Major, P., Baczko, I., Odening, K.E., Bodrogi, L., Hiripi, L., Varro, A., 2016; The potential impact of new generation transgenic methods on creating rabbit models of cardiac diseases. ProgBiophys Mol Biol 2016, in press, this issue
Baumgartner, C., Brandl, J., Münch, G., Ungerer, M., 2016; Rabbit models to study atherosclerosis and its complications- transgenic vascular protein expression in vivo. ProgBiophys Mol Biol 2016, in press, this issue
Lang, C.N., Koren, G., Odening, K.E., 2016; Transgenic rabbit models to investigate the cardiac ion channel disease long QT syndrome. ProgBiophys Mol Biol 2016, in press, this issue
Baczko, I., Jost, N., Virag, L., Bosze, Z., Varro, A.,2016; Rabbit models as tools for preclinical cardiac electrophysiological safety testing: importance of repolarization reserve. ProgBiophys Mol Biol 2016, in press, this issue
Gemmell, P., Burrage, K., Rodriguez, B., Quinn, T.A., 2016; Rabbit-Specific Computational Modelling of Cardiac Cell Electrophysiology: Using Populations of Models to Explore Variability in the Response to Ischemia. ProgBiophys Mol Biol 2016, in press, this issue
Arevalo, H., Boyle, P.M., Trayanova, N., 2016; Computational rabbit models to investigate the initiation, perpetuation, and termination of ventricular arrhythmia. ProgBiophys Mol Biol 2016, in press, this issue