Ion Channel Regulation in the Pathophysiology of Atrial Fibrillation: Using Mathematical Modeling as a Predictive Tool for Cardiac Disease
Year: 2017
Type: article
Abstract: Atrial fibrillation (AF) affects 2.5 million people per year in the U.S., and is associated with high morbidity and mortality.Both electrical and structural remodeling on the cardiac cell-and tissue-level contribute to AF, but the precise molecular pathways that lead to atrial fibrillation pathogenesis are not well understood.Mathematical modelling is ideally suited to understand the molecular basis of cardiac arrhythmias by allowing simulation of complex biological systems based on integrated data from individual populations of ion channels.A cross-platform multi-threaded graphical user interface LongQt was developed for advanced computational cardiac electrophysiology studies in sinoatrial, atrial, and ventricular cells to help bridge the gap between experimental and theoretical techniques in cardiac electrophysiology.A method of parameter sensitivity analysis is discussed to help define the contribution of individual ion channels to cell membrane excitability and action potential properties.Finally, a computational model of the human atrial cell was used to determine the mechanism for increased susceptibility to arrhythmogenic events in patients with defects in Ca 2+ /calmodulin-dependent protein kinase signaling pathways.An atrial computational model was extended to explore CaMKII activation of late sodium current (INa,L) and phosphorylation of downstream targets (L-type Ca 2+ channel, phospholamban, ryanodine receptor).Both LongQt and the method of parameter sensitivity analysis were used to help identify the cellular pathway responsible for disrupted ion homeostasis and afterdepolarizations in atrial cells.Intracellular Ca 2+ and Na + accumulation, increased phosphorylation of RyR2 by CaMKII, and abnormal Ca 2+ dynamics [e.g.beat-to-beat alteration (alternans)], and afterdepolarizations (early and late phase) was observed in marathon, I did not run this race by myself.I have an enormous appreciation for the people who lifted me up along the way, with whom I shared my highest and lowest moments and remained steadfast by my side.I should also mention that I procrastinated the most on this section, so if I missed anyone in these acknowledgements, it is not for lack of appreciation but due to lack of sleep.I am unbelievably lucky to have met some wonderful people during my time in graduate school, who are both good to me and good for the world.Thank you to Evan Jaffe for our travels, car trips, long talks, for playing music, for the Long Shot (this goes double for you, Jake Sours and Andrea Sanchez-Sours), for being so creative and reminding me that there is more to life than school.Thank you to Elena Chung for school and fashion advice, pictures of Shrimp, long walks around Easton, and being an inspiration to me in every way.Thank you to Alecia Blaszczak for being Wonder Woman (fierce, smart, strong, and does it all in heels), an unrelenting positive force, for our nights in the Short North and our days at the hospital cafeteria.Thank you to Zana Coulibaly for being a role model and hilarious friend for me in the early days of graduate school, and the shrimp buffet.Thank you to RB McGee for being my neighbor, drinking buddy, and a very inspirational yogimathematician extraordinaire.Thank you to Mark Calhoun, Lauren Cosby, and PeterAmaya for giving me a community within our department that I would not have discovered any other way, for always striving to greater heights, for leaving our community better than we found it, for sharing the trials and tribulations of graduate school and reminding each v other that we each have what it takes to make it through.Thank you to Alexis Burns and the women of WEGC for reminding me that regardless of how many of us there are, our world is beautiful, colorful, worth putting energy into, and as long as we work hard and stay sharp we can accomplish anything.
Author: Birce Önal
Institution: The Ohio State University
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W2899334911