The search for successful anti-arrhythmia therapeutics is rooted in the voltage clamp and current clamp techniques, which have provided the mechanistic details behind the ionic membrane currents that compose the cardiac action potential. We combined and coupled experimental and computational techniques to elucidate arrhythmia mechanisms. Traditionally, data such as cardiac action potentials, the cellular-level functionality that cardiac models aim to emulate, contains insufficient information to construct accurate models used to study arrhythmia. Here, we developed new experimental methods to extract information-rich data, which in turn were used to construct more accurate whole-cell and membrane current models.
First, investigated the global robustness of a cell to repolarize, termed “repolarization reserve”. Repolarization reserve has been well described in terms of ionic currents but has not been quantified by a standard metric. We developed and tested a novel method to quantify a cardiomyocyte’s total capacity for repolarization. We then show how this new metric can be used in pharmacological testing to determine pro-arrhythmia side-effects. We then optimized a whole-cell mathematical model of a ventricular cardiomyocyte using data obtained with dynamic patch clamp, a hybrid computational-experimental technique. Model predictions revealed how the balance between two currents, the rapid portion (IKr) and slow portion (IKs) of the delayed rectifier potassium current, dictate how cardiac cells respond to perturbations and their susceptibility to arrhythmias. Specifically, the ratio between IKr and IKs was shown to have a drastic impact on arrhythmogenic potential, even when a metric of whole-cell behavior, action potential duration, is the same. Finally, we examined how the balance between the delayed rectifier potassium currents changes from rest to exercise due to β-adrenergic stimulation. To do so, we developed a novel methodology that uses computationally verified experimental voltage clamp protocols and subsequent global reparameterization to construct more accurate models for each condition. Overall, we gained greater understanding in a major mechanism underlying arrhythmia, cardiac repolarization.
|Advisor:||Christini, David J.|
|Commitee:||Krogh-Madsen, Trine, Palmer, Lawrence, Accardi, Alessio, Aksay, Emre|
|School:||Weill Medical College of Cornell University|
|Department:||Physiology, Biophysics & Systems Biology|
|School Location:||United States -- New York|
|Source:||DAI-B 81/2(E), Dissertation Abstracts International|
|Keywords:||Cardiology, Dynamic patch clamp, Electrophysiology, Ion channels, Mathematical modeling|
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