Defining new insight into fatal human arrhythmia: a mathematical analysis

159 Pages·2016·8.28 MB·English

by  Roseanne Marie Wolf

University of Iowa
Iowa Research Online
Theses and Dissertations
2012
Defining new insight into fatal human arrhythmia: a
mathematical analysis
Roseanne Marie Wolf
University of Iowa
Copyright 2012 Roseanne Marie Wolf
This dissertation is available at Iowa Research Online: http://ir.uiowa.edu/etd/3013
Recommended Citation
Wolf, Roseanne Marie. "Defining new insight into fatal human arrhythmia: a mathematical analysis." PhD (Doctor of Philosophy)
thesis, University of Iowa, 2012.
http://ir.uiowa.edu/etd/3013.
Follow this and additional works at:http://ir.uiowa.edu/etd
Part of theApplied Mathematics Commons
DEFINING NEW INSIGHT INTO FATAL HUMAN ARRHYTHMIA: A
MATHEMATICAL ANALYSIS
by
Roseanne Marie Wolf
An Abstract
Of a thesis submitted in partial fulfillment of the
requirements for the Doctor of Philosophy degree in
Applied Mathematical and Computational Sciences
in the Graduate College of
The University of Iowa
May 2012
Thesis Supervisors: Assistant Professor Thomas J. Hund
Assistant Professor Colleen C. Mitchell
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ABSTRACT
Background: Normal cardiac excitability depends upon the coordinated activity
of ion channels and transporters. Mutations in genes encoding ion channels affecting
their biophysical properties have been known for over twenty years as a root cause of
potentially fatal human electrical rhythm disturbance (arrhythmias). More recently,
defects in ion channel associated protein (e.g. adapter, regulatory, cytoskeletal proteins)
have been shown to cause arrhythmia. Mathematical modeling is ideally suited to
integrate large volumes of cellular and in vivo data from human patients and animal
disease models with the over goal of determining cellular mechanisms for these atypical
human cardiac diseases that involve complex defects in ion channel membrane targeting
and/or regulation. Methods and Results: Computational models of ventricular, atrial,
and sinoatrial cells were used to determine the mechanism for increased susceptibility to
arrhythmias and sudden death in human patients with inherited defects in ankyrin-based
targeting pathways. The loss of ankyrin-B was first incorporated into detailed models of
the ventricular myocyte to identify the cellular mechanism for arrhythmias in human
patients with loss-of-function mutations in ANK2 (encodes ankyrin-B). Mathematical
modeling was used to identify the cellular pathway responsible for abnormal Ca2+
handling and cardiac arrhythmias in ventricular cells. A multi-scalar computational
model of ankyrin-B deficiency in atrial and sinoatrial cells and tissue was then developed
to determine the mechanism for the increased susceptibility to atrial fibrillation in these
human patients. Finally, a state-based Markov model of the voltage-gated Na+ channel
was incorporated into a ventricular cell model and parameter estimation was performed to
determine the mechanism for a new class of human arrhythmia variants that confer
susceptibility to arrhythmia by interfering with a regulatory complex comprised of a
second member of the ankyrin family, ankyrin-G. Conclusions: Ca2+ accumulation was
observed at baseline in the ankyrin-B deficient ventricular model, with pro-arrhythmic
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spontaneous release and afterdepolarizations in the presence of simulated β-adrenergic
stimulation, consistent with the finding of catecholaminergic-induced arrhythmias in
human patients. The simulations demonstrated that loss of membrane Na+/Ca2+
exchanger and Na+-K+-ATPase contributed to Ca2+ overload and afterdepolarizations,
with loss of Na+/Ca2+ exchanger as the dominant mechanism. In the atrial model of
ankyrin-B deficiency, the loss of the L-type Ca2+ channel targeting was identified as the
dominant mechanism for the initiation of atrial fibrillation. Finally, the simulations
showed that human variants affecting ankyrin-G dependent regulation of Na 1.5 results
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in arrhythmia by mimicking the phosphorylation of the channel. Most importantly,
mathematical modeling has been used to the molecular mechanism underlying human
arrhythmia syndromes.

Abstract Approved: ____________________________________
Thesis Supervisor
____________________________________
Title and Department
____________________________________
Date
____________________________________
Thesis Supervisor
____________________________________
Title and Department
____________________________________
Date
DEFINING NEW INSIGHT INTO FATAL HUMAN ARRHYTHMIA: A
MATHEMATICAL ANALYSIS
by
Roseanne Marie Wolf
A thesis submitted in partial fulfillment
of the requirements for the Doctor of Philosophy degree in
Applied Mathematical and Computational Sciences
in the Graduate College of
The University of Iowa
May 2012
Thesis Supervisors: Assistant Professor Thomas J. Hund
Assistant Professor Colleen C. Mitchell
Copyright by
ROSEANNE MARIE WOLF
2012
All Rights Reserved
Graduate College
The University of Iowa
Iowa City, Iowa
CERTIFICATE OF APPROVAL
_______________________
PH.D. THESIS
_______________
This is to certify that the Ph.D. thesis of
Roseanne Marie Wolf
has been approved by the Examining Committee
for the thesis requirement for the Doctor of Philosophy
degree in Applied Mathematical and Computational Sciences at the May 2012
graduation.
Thesis Committee: ___________________________________
Thomas J. Hund, Thesis Supervisor
___________________________________
Colleen C. Mitchell, Thesis Supervisor
___________________________________
Peter Mohler
___________________________________
Bruce Ayati
___________________________________
Rodica Curtu
___________________________________
Long Sheng Song
To Mom and Dad
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ACKNOWLEDGMENTS
First and foremost, I must thank my advisors, Thomas Hund, Ph.D. and Colleen
Mitchell, Ph.D. I could not have asked for better mentors. You not only taught me
mathematics, computer science, and electrophysiology, but you have been great role
models. The enthusiasm you have for research was contagious, and I quickly learned the
ups and downs. While there were challenging days, Tom was always there with a high
five for the mini-breakthroughs. I will forever be grateful of the example you have
provided as successful professors. I can only hope that someday I am able to pass on
what you have taught me to my own students, yet at the same time, I know there is so
much more for me to learn from you.
I must also express my gratitude to my committee, Peter Mohler, Ph.D., Bruce
Ayati, Ph.D., Rodica Curtu, Ph.D., and Long Sheng Song, M.D., M.S., for their guidance
and review of this work.
I also want to thank the past and present members of the Hund, Mohler, and
Anderson labs. They made coming to work each day enjoyable and I will miss their
support and fellowship.
To my biology friends – Paari Dominic Swaminathan, M.D. and Madhu Singh
Ph.D. From a chance conversation in the hallway, you have become lifelong friends.
Not only have you been there to answer my many questions about the heart, but you were
always there when I needed life advice. You have been through the ups and downs of the
past year with me and I couldn’t have done it without you. You have challenged me,
inspired me, taught me, and shared a laugh with me. Your friendship has helped me to
grow as a person and that’s more than I ever could have asked for.
To my math friend - Scott Small, Ph.D. Without you, I never would have
survived analysis. Thank you for your friendship and support and letting me claim your
office as mine. I can never repay you and I wish you the best of luck.
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And finally to my family, especially Mom and Dad - words cannot describe my
gratitude for your constant love. You have always encouraged me to keep going, even
when I didn’t think I could. You were my first teachers in life and have been with me
every step of the way. All of the sacrifices you have made through the years to provide
me with the best education have not gone unnoticed. You were the ones to teach me if I
worked for it, I will appreciate it much more than if it was given to me. Although I may
not have believed it at the time, I know now just how true it is. For all of the countless
phone calls, the headaches I may have caused, the food I stole from home, and the many
incidentals along the way, thank you. You have asked me so many times and I’m finally
able to say after all these years of school, I’m done.
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