Cardiac arrhythmias in ion channel dysregulation

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Concept

Meeting for brainstorming and task development: Sunday June 10, 6:30PM, Junior Common Room

Hi everyone, this is a project related to modeling cardiac tissue with the aim of attempting to understand the conditions under which pathological arrhythmias are evoked. These would include ventricular fibrillation and/or torsades de pointes. Specifically, it would be interesting to look at the the systemic effect of modulating myocyte function by altering specific ion channel parameters, though it would also be interesting to model the effects of myocardial infarction (dead/dying tissue in the heart due to heart attack).

Who's interested (add your name!)

• Vikas Shah
• Nathan Menke
• Kathryn Cooper
• Simon Angus
• John Mahoney
• Tim Johann
• Olaf Bochmann

Ventricular Fibrilation

Ventricular Fibrilation from wikipedia

http://upload.wikimedia.org/wikipedia/commons/8/85/EKG_VF.jpg

I have taken data from this trace for possible future comparison with our model.

* the cleaned-up data is available through email from me (s.angus AT unsw.edu.au) .. couldn't upload it because they have set tight permissions for .csv files.

Questions to answer

• Can we create a minimal but useful model of cardiac tissue that appears to have normal function?
• What are the effects of perturbing ionic concentrations?
• What are the effects of perturbing ion channel functions?
• What are the effects of perturbing topological characteristics of the model (e.g. "damaging" part of the "heart")?

Background reading

• The laboratory of Yoram Rudy and colleagues (http://rudylab.wustl.edu/research/cell/index.html)
  • [Here is a share] of many of the papers that are linked to on the Rudy website. In particular I think the Rudy and Silva review article from 2006 is very relevant to our project, as are the other two review articles.
  • Provide C++ and Matlab sources code for very detailed single cell models of canine and guinea pig cardiac ventricular myocytes. These single cell models include descriptions of Na+, K+, Ca2+, and Cl- ion flows. They account for both Ca2+ release from intracellular stores and influx from extracellular environment. They also handle other more esoteric details.
  • http://rudylab.wustl.edu/research/cell/publications/propagation.htm Provides details of published work in which multicellular cardiac systems were modeled, using their single cell models, in order to model various electrophysiological phenomenal.
  • http://rudylab.wustl.edu/research/cell/publications/mutations.htm Gives an overview of the publications of the group looking at the effects of altering single channel parameters in order to examine the mechanism of arrhythmogenesis. Na+, K+, and Ca2+ channels have been examined.

Brainstorming ideas

• Want to avoid using an overt 3D model if possible. 2D with wraparound edges can provide a cylindrical sheet of cells which may provide a useful starting point, with more complicated topology or iterations if necessary. Using a circular 1D model may also be an appropriate strategy.

Sangus 07:54, 6 June 2007 (MDT) nice idea

• • so this would potentially give rise to a topological/local-interactions basis for synchronization (or not) in activity. Could a patch of cells which are under-supllied of some key signal transmitter in turn cause others to delay .. is there a native control system for this problem, if so, what if this is disrupted?
• "Modular" model as opposed to use of differential equation methods.
  • This would be akin to a cellular automata model if in 2D -- each grid place reacting to local environmental conditions and reacting accordingly

Vikasnshah 20:51, 6 June 2007

• Absolutely there is a physiologic basis for local interactions. Cardiac myocytes have a structure called the intercalated disk between two adjacent myocytes. This structure is essentially just the abutment of the cell membranes, but it undulates and zigzags so that the effective surface area of the abutment is higher. The intercalated disk contains protein structures which make the cardiomyocytes electrically contiguous with one another (gap junctions). They also contain protein structures which make the cells tightly adherent to one another and to the contractility apparatus within the cells.

[Article on cardiac architecture and physiology]

The above article is a great review of cardiac histophysiology. There are an average of 11.6 intercalated disks per myocyte, indicating that there are both lateral (or transverse) and longitudinal, or end-to-end, electrical continuities between cells. There is an anisotropy in the observed propagation of action potentials through cardiomyocytes, such that the velocity of propagation is approximately three times faster longitudinally than laterally.

The article also provides a set of testable results to demonstrate the validity of any model that we develop.

Just to clarify, the Rudy group has done some work in multiple cell systems, and has a series of paper describing their results. As I go through some of these references I will post more information to the wiki. I will also post a copy of this email there.

Fundamentally, this project may not end up doing much that is new, although the specific mutation and mechanism of disruption that I worked on for my PhD thesis has not been examined using these modeling techniques. Depending on what we find, the results may or may not be publishable. However, because this is such a classic model system for a networked system that can exhibit chaotic behavior, it is probably a project worth pursuing.