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Self-restoration of cardiac excitation rhythm by anti-arrhythmic ion channel gating
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Authors
Rupamanjari Majumder*
Tim De Coster*
Nina Kudryashova*
Arie O Verkerk
Ivan V Kazbanov
Balázs Ördög
Niels Harlaar
Ronald Wilders
Antoine AF de Vries
Dirk L Ypey
Alexander V Panfilov
Daniël A Pijnappels
* = equal authorship
Funding
ERC starting grant 716509 (to DAP)
Our body protects itself constantly with the use of built-in mechanisms such as temperature regulation or fluid balance in the body. However, these mechanisms are limited in certain organs and associated biological processes. For example, the heart fails to self-restore its normal electrical activity once disturbed (such a disturbance might result in a sustained heart rhythm disorder). We wanted to remedy this shortcoming of the body by presenting proof-of-concept of a biological self-restoring system that allows automatic detection and correction of such abnormal excitation rhythms. Since this is a biological alternative to the workings of an ICD (small metal device that gets implanted in patients to reset their heart rhythm with an electrical shock), we call this the biological ICD or BioICD.
How to achieve termination?
To find such a system, we have to look a little deeper into a cardiac cell. Every cardiac cell has a membrane potential. This membrane potential can change over time and provides an electrical signal that can travel through the heart. To create the membrane potential, a cell has different pores in its membrane that allow ions to pass through (and hence these pores are called ion channels). When an electrical signal passes a cell, the cell excites and later restores itself back to rest. The change the membrane potential undergoes in that time is called an action potential.
To realize automatic detection and correction of abnormal excitation rhythms, we envisioned to integrate ion channels with newly designed gating properties into cardiac cells. This allows cardiac tissue to:
observe the difference between normal rhythm and rhythm disorder based on frequency
generate an ionic current for termination of the detected heart rhythm disorder.
This last mentioned action either means that we should stop a new action potential from forming. To do this, we can either suppress a new incoming action potential, or prolong the previous action potential such that the new one can not move forwards any more (since two action potentials can not exist in the same place at the same time). We chose the last option and went for frequency-dependent action potential prolongation (Figure 1). However, that poses the question how we can achieve such action potential prolongation.
Figure 1: The anti-arrhythmic action principle of the BioICD channel is shown here, where you can see action potential prolongation and subsequent termination of fast cardiac rhythm. The upper panels show how the wave dynamics look, where at the starred locations the action potential traces were measured and displayed at the bottom.
Accumulation is the solution
So how do we achieve this action potential prolongation? Well, we looked at mathematical formulations of ion channels and modified them such that we get the properties that we want. With the use of an accumulator that reacts to frequency, we were able to start producing extra current only after a certain threshold was reached (Figure 2). This extra current then made the action potential longer in the way it could be seen in Figure 1. The exact mathematical formulation makes use of Markov processes. However, there is not just one solution to the problem. We could design multiple mathematical ion channels that react to frequency and that prolong action potential (three are presented in the paper). However, since this is a first postulation of a new idea, we stuck to one model for working out what could be achieved if such an ion channel would exist.
Figure 2: The Markov chain that was used for the mathematical model of the BioICD channel. Its working can be seen on the right, where special attention should be paid at the black line (the open state O of the BioICD channel) that accumulates at high frequency but shows normal behavior under low frequencies.
What are the effects?
We tested this new ion channel virtually in a variety of situations. These situations ranged from spiral waves in healthy tissue to long lasting heart rhythm disorders, both in the upper two chambers of the heart (atria) and the lower two chambers of the heart (ventricles). In each of these situations we could see that upon fast rhythm, the new ion channel would activate itself and would rapidly and repeatedly restore normal excitation rhythm. It is important to note that under regular rhythm this ion channel didn't influence the action potential at all.
And what about real cells?
It is nice to have a mathematical model that behaves as we envisioned, but the real deal has to happen in a real cell. As a first step towards the realization of the envisioned ion channel, we relied on the experimental technique of dynamic patch-clamp. In dynamic patch-clamp, a real cell is connected to a computer, which can inject current into the cell at precise quantities and at precise times. This allows us to let the computer do the work of the newly envisioned ion channel. We tested on different cells and with different parameters and could terminate fast pacing rhythm in each cell we looked at (Figure 3).
To make sure that the new ion channel would not interfere with the pacing, we used cells that have an extra ion channel that reacts to light. When light shines on the cell, these ion channels activate the cell. This property was used to shine light at specific times to pace the cell at high frequencies. Since the rhythm was now controlled with light, and the BioICD current was injected through the patch-clamp set-up, the results of what we observed can be solely contributed to the BioICD current.
Figure 3: Validation of the BioICD concept in real cells with the use of the dynamic patch-clamp technique. (A) Human atrial cells that were used to carry out the experiments. (B) Dynamic patch-clamp set-up creating a feedback system for current injection and light pacing. (C) Typical membrane potential (Vm) and injected current (Iinj) traces with and without the BioICD current (IBioICD) enabled at 7 Hz. Both traces are from the same cell and were recorded 7 s apart. Dots indicate the pacing times. (D) Typical membrane potential and injected current traces with and without the BioICD current enabled in the same cell as (C) at 8 Hz. Also here, both traces were recorded 7 s apart. (E) Green light shows that the cell is active and reacts to light. (F) Zoom-in of the trace in (C) showing termination of fast pacing activity. The last optical stimulus is blocked, allowing 1 Hz activation to regain. (G) Maximal basic cycle length (BCL) for which termination still occurs as a function of baseline APD.
What does this mean?
Our study presents insight into acquired self-protective mechanisms to keep the heart in regular heart rhythm. This encompasses a variety of rhythm disorders that can be reset back to normal rhythm. We used an engineered ion channel to accomplish this feat, where the ion channel reacts to frequency to activate itself. Self-resetting of an acutely disturbed heart rhythm by such ion channels could provide unique insight into heart rhythm disorder management and could lay the foundation for the development of innovative treatment options by the creation of new biology for therapeutic purposes. The ultimate purpose of this fully biological approach would be acute, yet trauma-free termination of heart rhythm disorders.
With this study, we also stretched the field of synthetic biology into cardiology and provide a radically new perspective for other medical fields, given the general nature and versatility of biological self-regulating systems. This perspective involves that a diseased organ can create its own remedy, for example a Biologically Integrated Cardiac Defibrillator (BioICD) in case of the heart.
Journal info
Article type: Research Article
Impact factor: 7.94
ISSN: 2050-084X
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