Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43

Prudat, Yann; Kucera, Jan (2014). Nonlinear behaviour of conduction and block in cardiac tissue with heterogeneous expression of connexin 43. Journal of molecular and cellular cardiology, 76, pp. 46-54. Elsevier 10.1016/j.yjmcc.2014.07.019

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Altered gap junctional coupling potentiates slow conduction and arrhythmias. To better understand how
heterogeneous connexin expression affects conduction at the cellular scale, we investigated conduction in tissue
consisting of two cardiomyocyte populations expressing different connexin levels. Conduction was mapped
using microelectrode arrays in cultured strands of foetal murine ventricular myocytes with prede
fi
ned contents
of connexin 43 knockout (Cx43KO) cells. Corresponding computer simulations were run in randomly generated
two-dimensional tissues mimicking the cellular architecture of the strands. In the cultures, the relationship
between conduction velocity (CV) and Cx43KO cell content was nonlinear. CV
fi
rst decreased signi
fi
cantly
when Cx43KO content was increased from 0 to 50%. When the Cx43KO content was
≥
60%, CV became
comparabletothatin100%Cx43KOstrands.Co-culturingCx43KOandwild-typecellsalsoresultedinsigni
fi
cantly
more heterogeneous conduction patterns and in frequent conduction blocks. The simulations replicated this
behaviour of conduction. For Cx43KO contents of 10
–
50%, conduction was slowed due to wavefront meandering
between Cx43KO cells. For Cx43KO contents
≥
60%, clusters of remaining wild-type cells acted as electrical loads
thatimpairedconduction.ForCx43KOcontentsof40
–
60%,conductionexhibitedfractal characteristics,wasprone
to block, and was more sensitive to changes in ion currents compared to homogeneous tissue. In conclusion,
conduction velocity and stability behave in a nonline
ar manner when cardiomyocytes expressing different
connexin amounts are combined. This behaviour results from heterogeneous current-to-load relationships
at the cellular level. Such behaviour is likely to be arrhythmogenic in various clinical contexts in which gap
junctional coupling is heterogeneous.

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