Atrial Fibrillation

Atrial fibrillation (AF) is the most common cardiac arrhythmia, a class of conditions where the regular rhythm of the heart is interrupted. It refers to rapid and irregular electrical excitation of the atria - the upper chambers of the heart - which can reduce cardiac output (the amount of blood pumped in a single beat), decrease exercise tolerance and quality of life, and lead to stroke. AF is a progressive condition and is associated with other heart conditions such as Heart Failure. The variable presentation of AF and its complex multi-scale mechanisms make it a challenging condition to manage in the clinic and understand in the lab. My research uses computational modelling to understand the mechanisms of the initiation, progression and perpetuation of AF.

Understanding Atrial Fibrillation

In order to understand the dysfunction associated with AF, we must first cover some core concepts of the electrical activity of the heart.

Similar to skeletal muscle (those one's you use to move), the contraction of heart muscle is controlled by electrical excitation. As each cell receives a stimulus, it's spike in electrical activity - an Action Potential (below) - induces cellular contraction; the Action Potential is conducted from cell to cell, which are aligned in fibres to form the muscle tissue and Cardiac Conduction System (below). This controls the coordinated contraction of the heart, pumping blood around the body.

Concept: The Action Potential

Cardiac cells are encased by a cell membrane. Differences in the concentration of charged particles (called ions) inside and outside the cell result in a membrane potential - a difference in electric potential across the membrane. The Action Potential refers to the change in this membrane potential during excitation, illustrated below.

Animation: The Action Potential. Left panel shows a schematic of a cell with different types of ion and the channels which allow them to pass (coloured circles and channels), and the right panel shows the membrane potential at different stages of the Action Potential.

Ions can cross the cell membrane through specialised proteins (called ion channels), which can open or close to allow or prevent the passage of ions.

As ions flow through these ion channels, the movement of charge creates ionic currents which can change the membrane potential. Because the opening and closing of ion channels can also be controlled by the membrane potential, the currents can be coordinated to create the shape of the Action Potential.

There are multiple types of ion channel, each associated with specific ions (sodium, potassium, calcium and others).

"Inward" currents are those where positive charge enters the cell (yellow and red in the animation) - they make the membrane potential more positive, which we call “depolarisation”: Larger inward currents generally mean greater excitability and longer durations of the Action Potential.

"Outward" currents are those where positive charge leaves the cell (blue in the animation) – they make the membrane potential more negative, which we call "repolarisation": Larger outward currents generally mean lower excitability and shorter duration.

The balance of multiple different currents, controlled by the expression (amount of) each type of ion channel, can therefore control Action Potentials with different shapes and properties to match the varying requirements of cardiac function in different animals and under different conditions (e.g. rest versus exercise).

Concept: The Cardiac Conduction System

This refers to the specialised system within the heart which ensures it contracts in a coordinated manner to give the most efficient pumping function. By initiating the heartbeat in a specialised pacemaker region which spontaneously generates Action Potentials, and then conducting the excitation along specialised networks which can either delay or accelerate the propagation, a uniform and controlled contraction can be maintained.

Illustration of the cardiac conduction system. Source: here (public domain) Attribution: OpenStax College [CC BY 3.0 (]

On each heartbeat, the following process occurs:
  1. The electrical excitation is initiated in the "sino-atrial node", the natural pacemaker, located near the top of the right atrium.
  2. The excitation is conducted along preferential pathways in the atria (the upper chambers of the heart) and down to the "atrio-ventricular node", the only electrical connection between the atria and ventricles .
  3. As excitation spreads throughout the atria, they contract and the ventricles fill with blood.
  4. Conduction is delayed in the atrio-ventricular node to allow time for the ventricles to fill.
  5. After this delay, excitation is conducted rapidly to the apex (the bottom) of the ventricles, through the bundle of His, before quickly spreading through the Purkinje Fibres throughout the ventricle. This supports near-simultaneous activation of the entire ventricular mass.
  6. The heart then undergoes repolarisation (returning to the non-excited state), allowing the atria and ventricles to fill in preparation for the next beat.

So what is Atrial Fibrillation?

In normal conditions, electrical activation of the atria is controlled by the primary pacemaker. The electrical wave propagates from the pacemaker throughout the atrial tissue in a uniform and orderly manner. In Atrial Fibrillation, this regular rhythm is interrupted. Instead of the single, controlled excitation wave, multiple chaotic and non-uniform waves are observed. These override the natural pace-making function, result in non-coordinated and incomplete contraction of the atria, and send an irregular impulse to the ventricles which ultimately results in an irregular heart rate. Furthermore, due to the complex dynamics, it can be extremely challenging to terminate the behaviour in an attempt to return to sinus rhythm.

Mechanisms of Atrial Fibrillation

The complex and chaotic dynamics observed during Atrial Fibrillation - and the mechanisms by which they spontaneously emerge during regular rhythm - depend on the concepts of Focal Excitation and Re-entry. Focal excitation simply refers to spontaneous Action Potentials being generated in regions of the heart outside the pacemaker, and may occur much more rapidly than desired. Re-entry is more complex and involves irregular patterns which can self-perpetuate. These mechanisms are linked, and can drive excitation independent of the pacemaker. The dynamics of re-entry, and mechanisms by which it may be initiated, are dependent on a cellular property known as the Refractory Period.

Concept: Re-entry

Re-entry refers to complex patterns of cardiac excitation which follow a complete circuit and self-perpetuate, either transiently or indefinitely (illustrated in the animation below). Because it is independent of the natural pacemaker (it "overdrives" the excitation generated by the natural pacemaker because it is more rapid), it is not regulated properly and the rapid excitation leads to reduced relaxation times and thus inefficient pumping. If rapid and complex enough, such activity will almost entirely eradicate the pumping function of the heart, as each bit of tissue undergoes only minimal and unsynchronised contraction. It is this type phenomenon (including more complex versions) which underlies a cardiac arrest; the main purpose of a defibrillator is to terminate this activity.

Animation: Illustration of re-entrant excitation. The animation shows a 2D idealised sheet of cardiac tissue, representing, for example, the surface of the heart. The colours (purple-red-yellow) indicate the local voltage (a surrogate for contraction, as the voltage is the contractile trigger). On the left is a representation of normal behaviour: excitation originates from a single source and propagates through the tissue uniformly; there are significant rest periods between each excitation. On the right is an example of a simple form of re-entry - a "stable scroll wave". This type of excitation is rapid (note the minimal resting/relaxation period between each cell's excitation time) and, because it self-perpetuates, it is independent of the primary pacemaker.

There are multiple forms of re-entry including stable scroll waves (illustrated), rotation around an obstacle (e.g. a scar, or the valves at the junction of a blood vessel and the heart), and chaotic multiple wavelets. For this reason, it depends on both the single cell electrophysiology (the duration and shape of the Action Potential - including the refractory period; see next Concept) and the anatomical structure of the heart. Larger hearts (and shorter Action Potentials) increase the chances of re-entry both emerging and sustaining for a long period of time.

It is these interlinked complexities which make re-entry both a significant challenge to study and to manage, and such a suitable subject for computational modelling.

Concept: The Refractory Period

Animation: Illustration of the concept of the refractory period in single cells. This shows three cases where the first beat is identical, but the timing of the next stimulus varies (late - purple; just outside refractory period - blue; just inside refractory period - orange). The dotted line shows where the amplitude threshold is.

The refractory period (or effective refractory period, ERP) refers to the period of time after a cell has been excited during which it cannot be excited again. It is defined as the interval at which the amplitude of an action potential induced using a short-coupled stimulus (simply meaning a second stimulus within a short time-interval of the first) falls below a threshold relative to the first, usually 80%.

The video above illustrates this principal: when the second stimulus is applied appropriately late, it induces a full action potential (purple); as the coupling interval shortens, the amplitude of the induced excitation reduces (blue); at a certain interval, this amplitude falls below a threshold, and the resultant deflection is not considered a full action potential (orange).

So why is this an important feature? This 80% threshold of amplitude in single cells correlates with the sufficient excitation force for the action potential to propagate from cell to cell in tissue; when within the refractory period, the excitation is insufficient and the stimulus will not propagate along a strand of cells (video below). This protects the heart from being excited at rates which are too rapid for the contractile system to keep up.

In general, the longer the Action Potential, the longer the Refractory Period - small animals have shorter Action Potentials and Refractory Periods in order to maintain more rapid heart rates.

Animation: Illustration of the concept of the refractory period in tissue. On the left is shown the local voltage in a strand of cardiac cells (colours purple-red-yellow indicate local voltage). The stimulus is applied to the top edge, and propagates along the strand to the bottom edge. On the right are traces of the voltage from cells taken from different parts of the strand (indicated by the markers on the strand) - by the stimulus site (blue) and towards the far end (red).
The animation shows three different cases, all sharing an identical first beat (shown for each case), with the timing of the second stimulus varied (equivalent to that shown for the single cell video). The traces for the previous case are shown as semi-transparent lines, for comparison.
Note that the second stimulus propagates to the end of the tissue for the first two cases (outside the refractory period), but fails to propagate for the final case (within the refractory period).

Researching Atrial Fibrillation

Research on Atrial Fibrillation has been conducted throughout my post-graduate academic career, staring with my PhD project with Henggui Zhang (University of Manchester) and Oleg Aslanidi (King's College London). Now also in collaboration with Tony Workman (University of Glasgow) and Enric Alvarez-Lacalle and Blas Echebarria (BarcelonaTech), we develop models of atrial cells and tissues in order to study the interacting mechanisms which ultimately give the dysfunction associated with AF.

Mechanisms of re-entry in the atria

Compared to the ventricles, atrial tissue is observed to exhibit a larger degree of "electrical heterogeneity." This refers to the differences between Action Potential properties in different regions - for example, with some exhibiting long APs and others exhibiting short APs. Furthermore, the AP is observed to “remodel” (change) in AF patients, exhibiting substantially shorter durations across the whole atria. In a series of papers, we investigated the role of these two properties in the development and dynamics of electrical dysfunction during AF.

Specifically, it was hypothesised that the significant electrical heterogeneity could promote unidirectional conduction block (a precursor to re-entry) and may play a role in the initiation of sustained or transient arrhythmia events. Within this context, it was not clear how this mechanism would be modulated in combination with AF remodelling.

Concept: Unidirectional conduction block

The coupling between focal excitation and re-entry

Let's examine an idealised situation. Consider a sheet (just a 2D square) of tissue with two different regions, one with a short AP on the top half and a long AP on the bottom. How does this behave differently to a homogeneous sheet (one which has the same AP throughout)?

Considering what you have learnt about the refractory period, what will happen if we apply a stimulus to a small region at the junction between these two AP types, timed to be within the refractory period of the long region, but outside that of the short region??

Animation: Illustration of unidirectional conduction block due to heterogeneity. Two stimuli are applied to a homogeneous and heterogeneous sheet; the first is from the upper edge. It propagates uniformly through the tissue in both cases. The second is applied to a small region in the centre, at the junction between the region with a short AP (top half) and the one with a long AP (bottom half) in the heterogeneous case. Note that you can see this difference in the heterogeneous case following the first stimulus, by the bottom half staying active for longer than the top.

Whereas the first stimulus propagates uniformly in both cases, the second stimulus propagates uniformly only in the homogeneous condition; we can see it is temporarily blocked when trying to propagate into the longer AP region in the heterogeneous case. This is because this region is still within the refractory period, whereas the short AP region has recovered sufficiently for it to allow another excitation. This block does not last forever, and it does eventually enter this region. Note how asymmetric the conduction pattern is: it is this type of pattern which can degenerate into transient or sustained re-entry.

We can now see how focal excitation (spontaneous excitations emerging from where they shouldn't) can interact with tissue properties (such as electrical heterogeneity) to lead to re-entry, coupling the two phenomena. A potential mechanism for the spontaneous emergence of focal excitation is spontaneous intracellular calcium release.

Heterogeneity and re-entry in the human atria

In this publication, we demonstrated that regional differences in Action Potential Duration in human were sufficient for this mechanism to drive the development of re-entry following the application of short-coupled stimuli in specific locations.

Animation: Simulation of applying rapid stimuli to the junction between two atrial regions: the "Crista Terminalis", yellow, and the normal atrial tissue, blue, both shown in the left panel. The Crista Terminalis has a significantly longer AP (and refractory period) than the surrounding tissue. Applying multiple rapid stimuli to a small region on the junction of these tissue types resulted in significant conduction block and the eventual emergence of a full re-entrant circuit (right panel). Animation made from data associated with Aslanidi, Colman et al. 2011.

We also showed that these excitation patterns produced the typical ECG morphology associated with Atrial Fibrillation or Tachycardia.

This paper therefore demonstrated that electrical heterogeneity in the atria can promote the development of conduction abnormalities and possibly even sustained re-entry. This mechanism also highlights how, in-general, focal excitation - abnormal rapid stimuli - can be intimately linked with re-entry. There are multiple other mechanisms of conduction block (e.g. at the junction of a scar in the tissue, which will have poor electrical conduction properties and can also lead to unidirectional conduction block); focal excitation in combination with any of these mechanisms has the potential to lead to a transient or sustained re-entrant arrhythmic event. Note that whereas in the atria this is not immediately life-threatening, in the ventricles it is (and is referred to as a cardiac arrest).

The mechanisms which lead to natural focal excitation (i.e., not manually applying a stimulus, as above) form my primary current research interest, and is covered in more detail in Arrhythmia and Calcium; the remainder of the research described here pertains to what we call the "substrate" - the electrical and structural determinants of the way re-entry can form and how it behaves in the long-term, assuming the presence of focal excitation.

Related publications

[1] Aslanidi OV, Colman MA, Stott J, Dobrzynski H, Boyett MR, Holden AV and Zhang H. "3D virtual human atria: a computational platform for studying clinical atrial fibrillation." Prog Biophys Mol Biol, 2011, 107, 156–168.

Electrical determinants of re-entry dynamics

Patients whom exhibit persistent or chronic Atrial Fibrillation typically undergo permanent changes to their Cellular Electrophysiology - the term given to describe the whole system of ion channels and intracellular signalling which determines cellular electrical and mechanical behaviour. Described in detail in human by Tony Workman (among others), these changes in AF patients - termed remodelling - result in shorter Action Potential Duration and Refractory Period. Theoretically, shorter Refractory Periods more easily allow re-entrant circuits to both be sustained and cover a smaller circuit. However, it may also reduce the magnitude of heterogeneity, which can reduce the chances of a unidirectional conduction block leading to re-entry. Therefore, it is unclear what the overall effect of remodelling will be in terms of the vulnerability to the initiation and maintenance of AF due to this mechanism.

Figure: Left panels: Illustration of Action Potentials from three different atrial regions in a healthy person (top) and in a general, long-term chronic AF patient (bottom). Right panels: Example snapshots of simulated re-entry during AF with the healthy or chronic AF underlying electrophysiolgy. Data from Colman et al. 2013 J Physiol

In a publication comprising a substantial portion of my PhD research, the previously used model of the human atria was further developed to include descriptions of all of the major heterogeneous regions and multiple implementations of AF Remodelling. The simulation data demonstrated that with the inclusion of remodelling, substantial regional differences in Refractory Period remained in combination with short durations. This led to significant regions of high vulnerability to the induction of re-entry being combined with re-entrant circuits which sustained for longer and increased in complexity - patterns typical of chronic atrial fibrillation which result in significant risk to the patient and are extremely challenging to control.

One of the regions which exhibited the largest vulnerability to the initiation of re-entry was the Pulmonary Vein Junction - the location of the atria where the vessels taking blood from the lungs enter the heart. This region exhibits significantly different electrophysiology to the rest of the atria, and is also the most frequently observed source of AF in patients. In this publication, we demonstrated that the particularly short Action Potentials in this region being adjacent to the longer Action Potentials in the atria could be one reason for this prevalence of AF originating from the Pulmonary Vein Junction. There is significant research from many groups investigating multiple different properties of the Pulmonary Vein Junction which can account for this; in the research of mine and Oleg's research groups, we further studied two major features of this region: the complex fibre-structure and the presence of Atrial Fibrosis and are currently investigating factors which also promote Ectopic Activity in this region.

Related publications

[5] Colman MA, Aslanidi OV, Kharche S, Boyett MR, Garratt CJ, Hancox JC and Zhang H. "Pro-arrhythmogenic Effects of Atrial Fibrillation Induced Electrical Remodelling - Insights from 3D Virtual Human Atria." J Physiol, 2013, 591, 4249-4272.

Further work

Beyond those described above, I have worked with my collaborators on various other investigations of the mechanisms of AF and modelling the human atria. In this paper we also demonstrated, using a high-resolution reconstruction of the dog atria, that abrupt changes in fibre structure (cell orientation) can lead to conduction block and the development of re-entry. The impact of atrial fibrosis on arrhythmic conduction patterns was studied in this paper. A new computational model of the human atrial cell was developed in this paper, using extensive data provided from a congruent source. The impact of mutations associated with short-QT syndrome on human atrial conduction dynamics was investigated in this paper.

Check back soon for more updates and details about these works!