Learning resources

Here is where you will be able to learn all about the function of the heart, from basic conepts to research-level material. Currently, it only contains a list of the concepts introduced in the research pages, but there are plans to significantly expand this section. Keep posted if you are keen to learn!

Cardiac Electrophysiology

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 (https://creativecommons.org/licenses/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.

Concept: The intracellular Ca2+ handling cycle

The intracellular Ca2+ handling cycle is what couples the electrical and mechanical functions of a cell. Associated with each given cellular excitation (the Action Potential) is the intracellular Ca2+ transient (orange trace in the animation below), where the mechanical force follows this profile (with a delay). In order to maintain reproducible Ca2+ transients on every beat, cardiac cells require a sophisticated and regulated system to control the dynamics of the intracellular Ca2+ concentration. In broad terms, the system is determined by a process referred to as "calcium-induced-calcium-release" (described and illustrated below).

Animation: The intracellular Ca2+ handling cycle. Left panel shows a schematic of the cellular components involved in Ca2+ handling: the surface membrane and T-tubules (TT); the intracellular Ca2+ store called the Sarcoplasmic Reticulum (SR; blue-green); the contractile proteins (myofilaments); the Ca2+ carrying flux channels responsible for the initial influx (red), intracellular Ca2+ release (blue), SR refilling (yellow) and Ca2+ extrusion (green). Arrows indicate the timing and direction of fluxes. Green areas indicate high Ca2+ concentration. The right panel shows the Action Potential (blue) and whole-cell Ca2+ transient (orange) at each phase.

The Intracellular Ca2+ handling cycle:

  1. Influx: Ca2+ ions enter the cell during the AP, through openings of channels in the cell membrane which are primarily selectively permeable to Ca2+ ions (these are represented by the red channel in the illustration above and AP illustration previous).
  2. Release: Local elevation of Ca2+ concentration promotes binding with Ca2+-release channels (blue channels in the animation) on the surface of the intracellular Ca2+ store, the "SR"; these channels open, releasing a larger amount of Ca2+ from the store into the bulk intracellular space.
  3. Diffusion: This Ca2+ then propagates throughout the cell, filling the volume of the intracellular space.
  4. Contraction: This global elevation of Ca2+ concentration promotes binding with contractile proteins, called myofilaments, which hinge together to cause cellular contraction.
  5. Relaxation: During relaxation, Ca2+ is released from its binding sites with the myofilaments.
  6. And the resting levels of Ca2+ are restored through energy dependent ion-pumps which refill the intracellular Ca2+ store (yellow channels) and remove Ca2+ into the extracellular space (green channels).
All of these various fluxes must balance in order to maintain homeostasis; imbalance in these fluxes as well as degradation of the various protein function can result in failed coupling between the electrical and mechanical function and/or pro-arrhythmic behaviour (abnormal cellular dynamics which promote a loss of the regular rhythm of the heart).

Concept: The ECG

ECGs of healthy patients have a typical form, which may be familiar from representations of the ECG in popular media. The waveform consists of multiple different complexes, which correspond with the different phases of the cardiac conduction cycle.

Image adapted from here (public domain)

  • The first, small deflection corresponds to electrical activation of the atria (phases 1-3 in the description of the cardiac conduction system) and is called the "P-wave".
  • The delay in the atrio-ventricular node, while the ventricles fill (phase 4), results in a flat portion of the ECG, referred to as the "PR-segment".
  • The primary deflection in the ECG corresponds to the rapid ventricular activation (phase 5) and consists of three waves - the Q, R and S - referred to as the "QRS complex".
  • The time between ventricular activation and repolarisation then leads to another flat phase called the "ST-segment".
  • Finally, repolarisation of the ventricles (phase 6) leads to a final major deflection: the "T-wave".

The morphology (shape) and orientation of the different waves, and the relative lengths of the different segments, can provide important information about the state of a patient's cardiac conduction system. The morphology of the P-wave can provide information on the site initiating excitation in the atria; prolonged PR intervals can indicate heart block; inverted or variable T-waves can indicate abnormal repolarisation patterns.

Arrhythmia Mechanisms

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).

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.

Ca2+ Dynamics and Arrhythmia

Concept: Spontaneous Ca2+ waves

Individual ion channels are described by “stochastic dynamics”, that is, they are governed by probabilistic random state transitions (referring to the channel changing its form, for example, to allow or prevent the passage of ions). At the whole-cell scale, the thousands of channels present in the cell average out to give predictable and well-maintained deterministic behaviour. However, at the individual channel scale, no such averaging exists.

The Ca2+ system of cardiac cells contains a feedback mechanism which can amplify the effect of these probabilistic channel transitions: recall from the above description of the intracellular Ca2+ handling system that the release channels (red) are sensitive to Ca2+ while also releasing Ca2+ into the same volume to which they are sensitive. This has potentially disastrous consequences: random openings of single channels can elevate the local Ca2+ concentration sufficiently to trigger the opening of more channels and further release. This is what we call a Ca2+ “spark”.

Animation: Spontaneous calcium waves. The top panel shows an expanded schematic of the cellular Ca2+ handling system (as described previously). The bottom panel shows a simulation of a Ca2+ wave in the 3D volume of a cell. The right panels show the corresponding whole-cell averages for Ca2+ concentration (top; yellow), NCX current (middle; green) and membrane potential (bottom; red) at each stage of behaviour. What is shown are two non-propagating spontaneous Ca2+ sparks, followed by one which develops into a full-cell wave.

If the spark is sufficiently large, or appropriately timed relative to surrounding spontaneous sparks, then it can propagate throughout the cell as a wave. While this wave is propagating, the channels responsible for Ca2+ removal (green – “NCX”) are activated. These channels remove Ca2+ and result in a net inward current. Recall that inward currents act to increase the membrane potential. If the current is sufficiently large, this increase in membrane potential can trigger a full Action Potential, just as if the cell were stimulated. Spontaneous Action Potentials mean ones which are not activated by neighbouring excitation under normal conditions - they no longer are dependent on normal pacemaking for excitation. They can potentially lead to spontaneous excitations in tissue – the exact type of excitation which can trigger an arrhythmia event. Shown in the illustration is a spontaneous release which does not have sufficient amplitude to trigger a full Action Potential (which is more common than ones which do).

Concept: Ca2+ transient alternans

Ca2+ transient alternans refers to a dynamic behaviour in which the magnitude of the Ca2+ transient alternates on a beat-to-beat basis. This means that the contractile force developed by the cell also alternates on a beat-to-beat basis, between large and small contractions. This can interrupt the cardiac pumping function required by the body. Moreover, they can underlie Action Potential alternans – when the morphology and duration of the Action Potential alternates. If this is not synchronised between different regions of tissue, it can cause electrical conduction abnormalities which can lead to arrhythmia.

Whereas Ca2+ transient alternans are defined at the whole-cell scale (it is the magnitude of the whole-cell average which we are interested in), the behaviour is determined by spatial dynamics within the cell – each local cellular region either undergoes full or incomplete release (as a simplification), and it is the number of regions which undergo full release which determines the overall magnitude. Thus, Ca2+ transient alternans are characterised by spatial non-uniformity of the local concentration.

Figure: Example of Ca2+ transient alternans. The top panel shows the whole-cell average, whereas the bottom panel shows the underlying concentrations along the length of the cell.