Ionic basis of spontaneous electrical activity of cardiac muscle

This chapter is relevant to Section G2(i)  of the 2017 CICM Primary Syllabus, which asks the exam candidate to "explain the ionic basis of spontaneous electrical activity of cardiac muscle cells". Though the word spontaneous likely refers specifically to pacemaker cells with automaticity, the discussion also by necessity needs to go through the cardiac action potential of normal myocytes, mainly for contrast but also because almost all the SAQs on this topic ask for a comparison between the action potentials of a pleb myocyte and a specialised pacemaker cell. This territory has been a popular target for the First Part examiners, resulting in multiple past paper questions:

• Question 1 from the second paper of 2020
• Question 21 from the second paper of 2017
• Question 11 from the second paper of 2016
• Question 19 from the first paper of 2013
• Question 7(p.2) from the first paper of 2008

One can see the appeal of this for the examiners:

• There are clear right and wrong answers in this topic.
• There is a memorable diagram to test the candidates with.
• The ion channels and currents are all pharmacological targets and have clear clinical relevance.
• Discussion of antiarrhythmic drugs and other cardiac pharmacology builds on this knowledge, and so it can be considered fundamental. 

In summary:

The classic CICM question about this topic generally asks for the difference between pacemaker action potentials and those of the ventricular muscle. For one, they look markedly different:

In case somebody wants a real recording of such a waveform, this is the trace of the action potential generated by a single SA node cell, stolen from the excellent paper by Noma (1996).

In short, if one ever needed to list the differences between the action potentials of the ventricular myocyte and the pacemaker cells, the following list of features would suffice:

• The pacemaker cell slowly depolarises in Phase 4. In other words, there is no resting membrane potential - instead, there is a constant drift towards more positive values, mediated by the "funny current". 
• The depolarisation threshold is less negative. The pacemaker cells tend to depolarise when their membrane potential reaches -50 mV.
• The Phase 0 depolarisation is more gradual than the depolarisation of a ventricular myocyte. This is because the pacemaker cells lack functional voltage-gated sodium channels, and their depolarisation is mediated by L-type calcium channels, which open and close much more slowly.
• There is no Phase 1. 
• There is no Phase 2;  the peak positive membrane potential is sustained only for a very short period
• There is a steep rapid Phase 3, as the pacemaker cell repolarises. The final membrane potential at the end of Phase 3 is something like -60-65 mV, slightly less negative than the resting membrane potential of the normal working myocyte. This is usually referred to as the maximum diastolic potential, as it is the most negative potential during the pacemaker action potential cycle.

To summarise all this in a diagram:

Now, this diagram might give you the impression that the sympathetic and the parasympathetic nervous systems have a basically equal input into this activity, and that would be wrong. In fact, the parasympathetic nervous system is probably more important, at least in term of beat-to-beat baroreflex control of the heart rate. "More important" in the sense that the regulatory changes occur faster. Parasympathetic control requires only the activation of a ligand-gated channel (instantaneous!) whereas sympathetic control requires the painfully slow and laborious biosynthesis of a secondary messenger, over the timeframe of (probably) seconds. Observe:

For the sympathetic control, Noma (1996) offers an excellent discussion of the underlying ion channel mechanisms. The most important ionic player is If: the "funny current". This is the constant inward sodium / outward potassium flow which occurs via HCN channels (hyperpolarization-activated, cyclic-nucleotide–gated), and which is probably the most important difference between the pacemaker cells and the other myocytes. This channel is controlled by intracellular cAMP concentrations (hence the "cyclic-nucleotide–gated" bit), and is therefore the other major physiological lever on which the autonomic system pulls to control heart rate. Here is a representation of this effect from an excellent paper by Dario Difrancesco (1993):

But of course, that requires the synthesis of cAMP to act as a second messenger, which might take precious seconds. In contrast, the vagal input into pacemaker automaticity occurs via the I_K-Ach channel, which is a ligand-gated potassium channel. Acetylcholine activates this receptor more-or-less directly, by a G-protein mediated mechanism (Tomson & Arora, 2016). The upshot of this is that the activation of acetylcholine-gated potassium channels is essentially instantaneous, with the latency being totally due to the speed of neurotransmission, giving rise to an immediate change in heart rate. Here, in a fascinating study by Borst & Karemaker (1983), the simulation of the baroreflex produced a slowing of the R-R rate within 0.5 seconds.

Absolute and relative refractory periods

The refractory period, if one needed some sort of standar definition of it from the literature, can be described as:

"The property of reduced responsiveness to stimuli during particular phases of the excitatory processes"

- Antoni, 1996

In plain terms, this means that the myocyte which has just depolarised will not be inclined to depolarise again until a certain period of time has passed. This occurs for several reasons, but the main one seems to be the inactivation of the fast voltage-gated sodium channels, which undergo a conformational change after activating which takes some time (and a negative membrane potential) to reverse (Ulbricht et al, 2005).

In their weirdly prescriptive answer to Question 7(p.2) from the first paper of 2008, the college examiners blustered that "particular reference to the absolute and relative refractory periods was essential" in the discussion the Purkinje fibres. What were they talking about? Though all myocytes do certainly have absolute and relative refractory periods, there is something special about the refractory periods of Purkinje fibres to distinguish them from the rest. There are in fact several subdivisions of the refractory period, not all of which are apparent in every bog-standard myocyte, and if you specifically want to see the supernormal period, you really need to probe the Purkinje fibres. 

 In short, the subdivisions of the refractory period are:

• Absolute refractory period: where the threshold for depolarisation is infinite, i.e. no stimulus, no matter how great, will be able to make this myocyte depolarise again. This refractory period is mainly maintained by the obstinate refusal of voltage-gated sodium channels. They will simply not reopen for anything until the membrane potential has dropped to below -40mV.
• Relative refractory period: where stimuli of normal magnitude do not produce any depolarisation, but unnaturally large stimuli can still produce a depolarisation of a lower magnitude. This is because there are fewer sodium channels available (some will still be in their refractory state), and so it takes a larger stimulus to activate them and trigger a depolarisation. When such a depolarisation does occur, there are still too few sodium channels available to make for a "proper" Phase 0 spike, and so the depolarisation ends up being a bit anaemic, of a lower amplitude than the normal Phase 0 spike. Here are some direct recordings of such poor attempts at depolarisation during the relative refractory period, measured by Moore et al (1965) in a canine Purkinje fibre:
  
  As you can see, the resulting action potentials are clearly of a poorer quality than the normal ones, and potentially not sufficient to activate neighbouring cells. Which brings us to the next subdivision of the refractory period:
• Effective or "functional" refractory period: this is the period during which the cell cannot produce an action potential which could depolarise surrounding muscle. That could be either because depolarisation is completely impossible, or because it ends up being so useless that it cannot trigger the depolarisation of adjacent cells. Thus, this period incorporates the absolute refractory period, and then some fraction of the relative refractory period. It can sometimes be referred to as a "functional" refractory period.  
• Supranormal period: this is mainly seen in Purkinje cells. The repolarisation of these cells seems to reach a nadir which is slightly below the resting membrane potential. This creates a hyperexcitable period during which a weaker, subnormal stimulus could trigger depolarisation and produce an action potential. Weidmann (1955) were the first to describe this, and two years later Cranefield et al (1957) determined that this phenomenon was potentially the effect of stimulating the experimental fibres with a sufficiently powerful anode (i.e. it may not even exist in vivo). It is occasionally mentioned in textbooks, and the CICM trainee probably needs to be dimly aware of it. 

This can be expressed in the form of a diagram. The action potential on the left was constructed from several modern resources; the black and white curve on the right is an original measurement from Weidmann et al (1955), illustrating the supernormal period.

What is the point of all this? Well: with a refractory period like this, the likelihood of premature depolarisation is decreased, which means your myocardium can reliably expect a reasonably long period of relaxation before it needs to contract again. Ergo, diastolic filling can occur. If an ectopic pacemaker fires up somewhere and produces an action potential shortly after the last one, it will have nowhere to go, because in every direction there is unreactive refractory tissue. This property of cardiac muscle is therefore an important barrier to arrhythmogenesis, protecting the myocardium from "circus movement" arrhythmias like VT and flutter.

Compensatory pause following ventricular ectopic complexes

The compensatory pause is a phenomenon which was mentioned in the college answer to Question 7(p.2) from the first paper of 2008 as something which would have attracted additional marks. This is an interruption of the normal rhythm which occurs following an ectopic ventricular beat, and is the result of the refractory period of the ventricular myocytes.

In summary:

• A ventricular pacemaker fires for whatever reason, and you get a nice broad QRS complex because the ventricles depolarised abnormally.
• As the next normal SA node action potential arrives to the AV node, it finds the ventricle in the refractory period following the ventricular extrasystole, and dies because it cannot propagate any further.
• Therefore, the ventricle now has to wait until the next SA nodal action potential
• This delay (up to twice the normal R-R interval) is the compensatory pause.

Overdrive suppression

The Purkinje cells have an action potential which looks a lot like the myocyte action potential, but - like the pacemaker cells - the Purkinje cells have the capacity to spontaneously depolarise by means of a "funny" current. This automaticity is usually concealed by the slow depolarisation rate of these cells - normally firing at a rate of only about 40-50, they are usually bullied into obedience by the much faster sinus node rhythm. However, if the dominant pacemaker (SA node) suddenly stops firing, the "subsidiary" pacemakers elsewhere do not immediately take over - there is instead a pause before they start firing rhythmically at their low native rate. Clearly, some mechanism must keep these subsidiary pacemakers from making pace, while the SA node is still in control.

This phenomenon is called overdrive suppression. Mario Vassale (1977) explains it much better, but in summary, the mechanism behind overdrive suppression are as follows:

• Say, a Purkinje cell is being depolarised regularly by a high rate pacemaker like the SA node, at a rate higher than its innate rhythmicity.
• The high requency of the arriving action potentials produce a higher net sodium influx into this Purkinje cell, and so there is a high net concentration of sodium in that cell during a given time interval.
• This increased sodium stimulates sodium removal (and potassium uptake) by Na⁺/K⁺ ATPase, as that is it's job.
• Because this pump transfers 3 sodium atoms for every 2 potassium atoms, it is electrogenic- i.e it produces a net negative charge in the cell.
• Because there is more sodium to act as the substrate for this process, this increase in Na⁺/K⁺ ATPase activity has a hyperpolarising effect, i.e. the maximum diastolic potential of the pacemaker cell ends up more negative than it would otherwise be.
• Because the If funny current still works at the same rate, it therefore takes longer to bring the Purkinje cell up to its depolarisation threshold, and this produces the abovementioned pause.
• If the high rate pacemaker stops pacing at such a high rate, the Purkinje cell starts firing automatically at a slower rate, the net sodium content decreases, hyperpolarisation stops and the cell starts firing without long pauses at its innate (slow) rate.

The explanation of this concept may or may not benefit from a diagram: