ARRHYTHMOGENESIS IN NON-UNIFORM CARDIAC TISSUE EXHIBITS A HIGHLY NON-MONOTONIC DEPENDENCE ON EXTRACELLULAR POTASSIUM.

M. Miragoli, G. Gaudesius, S. Rohr.

Dept. of Physiology, University of Bern , Bühlplatz 5, CH-3012 Bern , Switzerland.  

It is well known that disorders in extracellular potassium concentration ([K+]o) and non-uniformities in cardiac tissue structure favor the occurrence of cardiac arrhythmias. Whereas arrhythmogenic mechanisms underlying either of these pathological settings have been extensively characterized in the past, it is not known how the simultaneous presence of both conditions affects arrhythmogenesis.This question was investigated in non-uniform cardiac tissue structures consisting of strands of cardiomyocytes merging with large tissue expansions which were designed in neonatal rat heart cell cultures using patterned growth techniques. Preparations were stimulated at 1 Hz in either anterograde (strand->expansion) or retrograde (expansion->strand) direction and impulse propagation characteristics at increasing levels of [K+]o were assessed using multisite optical recording of transmembrane voltage. The success of impulse conduction across tissue expansions displayed a highly non-monotonic dependence on [K+]o in the range of 1.45 to 29 mM. Unidirectional conduction blocks (UDBs) in anterograde direction were present at low [K+]o (1.45 - 2.9 mM), moderately elevated [K+]o (8.7 - 11.6 mM), and highly elevated [K+]o (23.2 - 29 mM). At low [K+]o, UDBs resulted from the enlargement of the current sink (expansion) due to the increase of the depolarizing charge required to reach activation threshold of sodium channels. At moderately and highly elevated [K+]o, UDBs were precipitated by a reduction of the current source (strand) due to increasing inactivation of sodium and calcium inward currents, respectively. Between these three levels of [K+]o, current source and current sink were sufficiently balanced as to permit successful bidirectional conduction. In agreement with these findings, sustained reentrant excitation in preparations with an anatomically fixed reentrant pathway could be elicited at all three levels of [K+]o inducing UDB whereas, at intermediate [K+]o, the absence of UDBs prevented initiation of reentry. Thus, in contrast to uniform cardiac tissue, where an increase in [K+]o ends with irreversible conduction block, the same intervention induces a complex sequence of repeated blocking and unblocking of anterograde conduction in non-uniform cardiac tissue due to a differential modulation of the current source and the current sink. This surprising behavior is likely to contribute to arrhythmogenesis during hypokalemia and to the intricate sequence of arrhythmic events accompanying acute myocardial infarction.