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Potassium channel blockade amplifies cardiac instability numerical studies of torsades de pointes
C F Starmer1, M R Reddy, A Namasivayam
1Division of Biomedical Engineering, Indian Institute of Technology, Madras.
Abstract:
Suppression of responses to premature stimulation has been the guiding principle in managing many cardiac arrhythmias. Recent clinical trails revealed that sodium channel blockade increased the incidence of re-entrant cardiac arrhythmias resulting in sudden cardiac death, although the physiologic mechanism remains uncertain. Potassium channel blockade offers an alternative mechanism for suppressing responses to premature stimuli. We have developed a simple model of a 2D sheet of excitable cells. We can initiate re-entrant activation with stimuli timed to occur within a period of vulnerability (VP). Reducing the Na conductance increases the VP while reducing the K conductance increases the collective instability of the array, and arrhythmias similar to torsades de pointes seen in patients subjected to K channel blocked can be readily initiated. Thus, while K channel blockade may suppress excitability by prolonging the action potential duration, it appears to simultaneously exhibit proarrhythmic properties that result in complex re-entrant arrhythmias.
Insights
Potassium channel blockade may suppress cardiac arrhythmias but can paradoxically increase instability, leading to dangerous re-entrant arrhythmias like torsades de pointes. This highlights potential proarrhythmic effects despite prolonging action potential duration.
Area of Science:
- Cardiovascular Physiology
- Computational Biology
- Electrophysiology
Background:
- Cardiac arrhythmias are often managed by suppressing responses to premature stimulation.
- Sodium channel blockade has unexpectedly increased re-entrant arrhythmias and sudden cardiac death, with unclear mechanisms.
- Potassium channel blockade presents an alternative strategy for managing premature stimuli.
Purpose of the Study:
- To investigate the proarrhythmic potential of potassium channel blockade.
- To model the effects of ion channel modulation on cardiac re-entrant arrhythmias.
- To understand the physiological mechanisms underlying potassium channel blockade-induced arrhythmias.
Main Methods:
- Development of a 2D computational model of excitable cells.
- Simulation of re-entrant activation initiated by premature stimuli within a vulnerable period (VP).
- Analysis of the effects of reduced sodium (Na) and potassium (K) conductance on VP and array stability.
Main Results:
- Reducing Na conductance was found to increase the VP.
- Reducing K conductance increased the collective instability of the cellular array.
- Simulations readily initiated arrhythmias resembling torsades de pointes under conditions of K channel blockade.
Conclusions:
- Potassium channel blockade, while potentially suppressing excitability by prolonging action potential duration, exhibits proarrhythmic properties.
- This blockade can lead to complex re-entrant arrhythmias due to increased cellular array instability.
- The findings suggest caution with potassium channel blockade as a therapeutic strategy for certain arrhythmias.