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:
One can see the appeal of this for the examiners:
In summary:
A Comparison of the Ionic Events
During the Cardiac Action Potentials
in the Myocyte and the Pacemaker CellCell Ventricular Myocyte Pacemaker cell Shape of the AP Resting potential -90 mV -60 mV Threshold Potential -70 mV - 40 mV Phase 4
- Resting potential
- Stable plateau
- Maintained by the Ik1 inward rectifying potassium current
- Slow depolarisation
- Maintained by the If "funny" sodium curent
Phase 0
- Rapid depolarisation
- Mediated by fast voltage-gated sodium channels
- Slow depolarisation
- Mediated by L-type calcium channels
Phase 1
- Rapid repolarisation
- Mediated by transient outward potassium currents (Ito) and the
- No Phase 1 in the pacemaker action potential
Phase 2
- Prolonged plateau at ~ 0mV
- Lasts ~ 100-200 msec
- Mediated by L-type calcium channels
- No real Phase 2 in the pacemaker action potential
Phase 3
- Rapid repolarisation
- Mediated by the Ikr, Iks and Ik1 potassium currents
- More gradual repolarisation
- Mediated by the Ikr, Iks and Ik1 potassium currents
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:
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 IK-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.
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"
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:
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.
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:
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:
The explanation of this concept may or may not benefit from a diagram:
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