Ion channel basis for alternans, memory and alternans control in individual cardiac myocytes: A computational study

Beat-to-beat alternation in action potential amplitude and morphology (alternans) in individual cardiac cells may be important in the development of cardiac arrhythmias. So far, it has been difficult to identify the cause for alternans at the ion channel level because computer models and experiments that display alternans also simultaneously exhibit other confounding rhythm patterns. To address this difficulty, we have developed an eigenmode method to study the dynamics of detailed cardiac cell models under constant pacing. The method completely separates these effects from one another in the linear regime, allowing each to be studied individually. We applied the eigenmode method to both the Beeler-Reuter (BR) and Canine Ventricular Myocyte (CVM) ion channel models to investigate the mechanism by which alternans is produced under conditions of constant, rapid pacing.; For the BR model, alternans was found to be rooted in the opposite phasing of the x1 and f gate perturbations that produces constructive interference between the slow outward and slow inward currents. For the CVM model, we discovered a new mechanism that amplifies small perturbations in the membrane potential in the early plateau through the action of potassium currents leading to a much greater potential perturbation during repolarization. Alternans in the CVM model is then found to be characterized by the coupling of action potential alternans with alternans in the intracellular calcium dynamics through the L-type calcium channel via the mechanisms of calcium induced calcium release, calcium dependent inactivation, voltage dependent activation and this membrane potential perturbation amplification mechanism. We also demonstrate that the amplification mechanism can be used to our advantage to control alternans. We find that the best time to apply the control stimulus is not during the repolarization phase of the action potential, as might otherwise have been expected, but rather during the early plateau phase, when the charge requirements are two orders of magnitude smaller.; The understanding of ion channel basis of alternans can provide new directions for the development of new treatments to cure dangerous cardiac rhythm disorders.