Multi-Scale Cardiac Electrophysiology: Bridging the Scales to Decipher Arrhythmia Mechanisms
- Author(s): Vincent, Kevin Patrick
- Advisor(s): McCulloch, Andrew D;
- Omens, Jeffery H
- et al.
Cardiac arrhythmias are a major source of morbidity, mortality, and healthcare cost in the United States. Arrhythmias are inherently multi-scale phenomena where cellular and subcellular abnormalities result in pathological impulse propagation. The failure of clinical therapies to sufficiently prevent or terminate arrhythmias is due, in part, to a lack of understanding of the underlying mechanisms. Integrating experimental results across spatial and temporal scales using computation modeling presents an important paradigm for investigating arrhythmia mechanisms. In this dissertation, computational modeling and experimental data at the subcellular, cellular, and tissue scales are used together to gain insight in to mechanisms of arrhythmias for clinically relevant cardiac diseases.
On the cellular and subcellular scale, the ability of caveolin-3 to modulate action potential duration through ion channel regulation was investigated using action potential models to interpreting ion channel data. Two examples are presented in Chapter 2. In the first example, a mouse ventricular action potential model is able to link changes in Kv4.3 channel expression to observed QT shortening from the electrocardiogram of caveolin-3-overexpressing mice. The second example parameterizes ionic currents in a human ventricular action potential model with patch clamp data from ion channels co-expressed with Long QT Syndrome causing mutations in caveolin-3. The results identify slowed calcium-dependent inactivation of the L-type calcium channel as an potentially arrhythmogenic mechanisms.
Integrating the subcellular, cellular, and tissue scales for multi-scale cardiac electrophysiology modeling presents numerical, computational, and physiological challenges. Chapter 3 examines these numerical challenges and presents a new high order finite element method to potentially reduce computational expense. This multi-scale electrophysiology solver is used to investigate the behavior of electrical rotors in the human atria in Chapter 4. Specifically, discontinuities in the fiber architecture of the right atria are shown to anchor rotors.
Transgenic mouse models present a unique ability investigate genome effects on the tissue scale. The final two chapters provide literature reviews aimed towards future work investigating triggered arrhythmia mechanisms. Chapter 5 reviews the mechanisms of CaMKII mediated afterdepolarization in cardiac disease. Finally, Chapter 6 provides a detailed methodological review of Langendorff perfusion and optical mapping of ex-vivo transgenic mouse hearts.