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Mechanisms of cardiac impulse propagation: the role of connexins

English title Mechanisms of cardiac impulse propagation: the role of connexins
Applicant Kléber André
Number 120253
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 01.04.2008 - 30.06.2010
Approved amount 353'184.00
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Keywords (4)

tissue engineering; Cardiac Remodeling; Connexins; Electrophysiology

Lay Summary (English)

Lead
Lay summary
Connexins form intercellular gap junction channels that allow diffusion of molecules up to approximately 1 kDa and exchange of electrical current. In the heart, 4 different connexins are expressed, Cx43, Cx40, Cx45 and Cx30.2 (mouse Cx30.2, human Cx31.9). The intercellular gap junction channels assure normal electrical excitation and subsequent contraction. Cardiac arrhythmias, such as arrhythmias in heart failure, after myocardial infarction and in atrial fibrillation are a frequent cause of morbidity and mortality, especially in the older population. The disturbances of electrical function causing these arrhythmias result from molecular and structural remodeling in which ion channels and transporters as well as connexins are involved. Both theoretical and experimental studies have shown that homogeneous decrease in cell-to-cell coupling by connexins leads to very slow conduction, a prerequisite for the generation of small, self-sustained re-entrant arrhythmogenic excitation. However, experiments in mice have suggested that arrhythmogenesis with reduced cell-to-cell coupling by connexins is a complex process and attributed a crucial role to the heterogeneity of connexin expression. In fact, heterogeneity in cell-to-cell coupling may be more important for arrhythmogenesis than a global reduction. A further complexity has been related to the interaction between cardiac connexins. In atrial tissue, Cx43 and Cx40 are expressed that can each form high conductance pores in artificial expression systems. However, the combined expression of Cx43 and Cx40 in atrial myocardium leads to mutual interaction and to a lower resulting conduction velocity than expression of Cx40 alone. The mechanism of this interaction has not been clarified in atrial tissue. This grant application has 3 aims: The first aim is related to the development of a technique that allows engineering of the cell-to-cell interface, cell shape and cell size in pairs and 2D strands of cultures synthetic murine heart tissue. This technique, currently in the stage of development, will enable (i) far better quantification of parameters determining propagation and a more accurate and detailed comparison of experimental results with results of theoretical simulations, (ii) vastly improved access of the cell pairs by voltage clamp electrodes, and (iii) rigorously controlled engineering of cell shape, cell size and intercellular coupling for potential future use in tissue repair. The second aim will provide information about the role of heterogeneity in Cx43 and Cx45 in ventricular impulse conduction. The third aim will define the mechanism(s) of Cx40 and Cx43 interaction in atrial tissue. All experiments proposed in this application follow from our previous work using synthetic murine heart tissue and the definition of the role of Cx43 in ventricle and of Cx43 and Cx40 in the atria. Accordingly, preliminary results are presented for aims 1 and 2.
Direct link to Lay Summary Last update: 21.02.2013

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Associated projects

Number Title Start Funding scheme
107918 Basic mechanisms of cardîac impulse propagation and arrhythmogenesis 01.04.2005 Project funding (Div. I-III)

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