Ischemic modulation of vulnerable period and the effects of pharmacological treatment of ischemia-induced arrhythmias: a simulation study.
First identified in the 1930s (Ferris et al., 1936 and Wiggers and Wegria, 1939), the concept of vulnerability applies perfectly to biological oscillators. We can safely say that vulnerability is an inherent property of any excitable media. The duration of vulnerable period (VP) (the time interval during which single stimuli can initiate self-sustaining propagation) is sensitive to medium properties and stimulus parameters (stimulus field, timing behind the conditioning wave, and stimulus amplitude). Apart from medium properties and stimulus characteristics, heart vulnerability is affected by any intervention targeting the excitatory and recovery process. Therefore, we can expect that any pathological condition disturbing heart excitation or tissue recovery will most probably alter the duration of VP. In this paper, we shall explore the implications of ischemia and one of the arrhythmia counteracting methods widely used in clinical practice-antiarrhythmic drugs--in changing the boundaries of VP. The Cardiac Arrhythmia Suppression Trial (CAST) studies, as well as classification based on functional characteristics, revealed the arrhythmogenic potential of both Class I and Class III agents, but failed to identify the proarrhythmic mechanisms. This study presents results from a mathematical model (Cimponeriu et al., 2001) of the ventricle based on Luo-Rudy cellular formulation Luo and Rudy, 1991) modified for studying the ischemic modulation of VP and the effects of pharmacological treatment of ischemia-induced arrhythmia. Simulations revealed the link between the cellular antiarrhythmic properties and the proarrhythmic effect at the multicellular level in the case of Na+ channel blockade. Na+ channel blockade delayed recovery of cellular excitability, but also introduced a nonuniform dispersion of refractoriness along the cardiac fiber that can serve as a substrate for initiating a new arrhythmia. Our initial analysis proved that fast unbinding rates are essential in reducing the proarrhythmic potential of Class I drugs. However, further investigations led us to believe that binding properties are equally important. An antiarrhythmic drug with high affinity for drug-channel complex formation elicits a higher level of blockade per time unit. Under this light, we hypothesize that even the modern, fast unbinding drugs are not necessarily safe.
Cimponeriu, A; Starmer, CF; Bezerianos, A
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