This chapter is vaguely related to Section G2(ii) of the 2017 CICM Primary Syllabus, which asks the exam candidate to "describe the normal and abnormal processes of cardiac excitation and electrical activity". Specifically, it is focused on fast voltage gated sodium channels, which are an essential element of those processes. One might think that for the specific purposes of the CICM exams it would be enough to know that these channels are ubiquitous, critically important as drug targets, and have a refractory period. But from the comments of the First Part examiners in Question 5 from the second paper of 2022, it would appear that candidates need to submerge into deep sodium channel lore.
Structure of the voltage-gated sodium channel
- Heteromeric transmembrane protein (Nav1.5)
- Made up of a larger (260 kDa) α subunit and two smaller (30 kDa) β-subunits
- Functionally important elements include:
- Extremely narrow (4.6 Å2) sodium-selective pore
- Activating gate (m gate)
- Inactivating gate (h gate)
Three states of activity:
- Resting state:
- m gate is closed and h gate is open; the channel is ready to be opened
- Open state:
- Opening is triggered by voltage (threshold of -60 to -70 mV)
- Starts with the opening of the m gate ("helical screw" or "sliding helix" mechanism)
- Permits flow of sodium ions
- Stops abruptly within a few milliseconds because of the time-triggered closure of the h gate
- Inactivated state:
- Closed h gate; flow of sodium ions is impossible
- This state ends after 100-140 milliseconds
- A time-triggered opening of the h gate and closing of the m gate returns the channel to the resting state
- The absolute refractory period: h gate is closed, and no depolarisation is possible
- The relative refractory period is the short late period of Phase 3 during which a supranormal stimulus can still produce a depolarisation of the myocyte, which will be of a sub-normal amplitude because only some of the fast sodium channels have entered a resting phase, whereas other have not.
- The effective refractory period is the period during which the cell either is unable to depolarise, or - if it does depolarise - the amplitude of the depolarisation is so depressed that it could not possibly depolarise any surrounding cells.
From the perspective of those frantic last minutes before the exam, this chapter is probably pointless, as that time would be better spent memorising lists of pharmacokinetic information and cramming respiratory equations into their short-term memory. From that, it follows that any reader who has decided not to skip this chapter is probably not experiencing any sort of time-pressured panic, and can peruse the literature in a relaxed manner. For these lucky people, one can recommend Yu & Catterall (2003) or Andavan & Lemmens-Gruber (2011), which were the most helpful in creating the summary that follows.
Yu & Catterall (2003) describe this group of proteins to an excellent level of detail, and the reader who needs to know All The Things is referred there instead. For the CICM trainee, it will be sufficient to know that these are everywhere. In general these channels are ubiquitous in essentially everything that has any sort of nervous system or excitable tissue, starting with jellyfish, and in fact excitable tissues are mainly excitable because they are able to express these proteins. They are present on the surface of myocytes in truly vast quantities (Makielski et al counted around 100,000 per cell) and are therefore able to mediate a massive rapid flux of ions. The specific variety seen in the mammalian heart is the Nav1.5 isoform (Zimmer et al, 2014), and there are currently nine individual isoforms identified in humans, named named Nav1.1 through Nav1.9.
Again, it would be fairly pointless to reproduce diagrams of this thing here, as CICM exam candidates would never be expected to reproduce them in the written paper, and the interested reader is referred to professional resources such as Jiang et al (2020), who do a much better job of this. If the candidate had to produce a brief written description, it would probably contain the following essential elements:
To answer the very valid question "what could be the relevance of all this to the intensivist", the reader is reminded that mutations of these channels often cause the kind of disease that lands you in the ICU, and the critical care practitioner must be at least dimly aware of the possibility that these are heritable, which bring about the need to - for example - test the entire family of a patient who, at a young age, had an unexplained cardiac arrest.
What's so special about this Nav1.5 variant, that is so structurally or functionally significant? Well. The short answer is, not much. It is not very different from the Nav1.4 isoform that appears in skeletal muscle, and in fact immature skeletal myocytes seem to express Nav1.5 until it gets replaced by 1.4 in the adult. Moreover Nav1.5 is not a "special" cardiac channel, and all kinds of sub-variations on the theme of Nav1.5 exist in the brain, for example. The most important aspect to explore is the different affinity these channel isoforms have for different drugs which we use to block them. For example, one could point out that variants 1.1, 1.2, 1.3 and 1.7 are all highly sensitive to tetrodotoxin, whereas 1.5, 1.6, 1.8 and 1.9 all have varying degrees of tetrodotoxin resistance. Sure, we don't tend to use much tetrodotoxin in our clinical practice, but there are other drug selectivity matters to mention:
Catterall & Swanson (2015) is where most of this information has come from, and the interested reader is redirected there.
The voltage gated sodium channel is so called because it conducts mainly the traffic of sodium. That seems like an extremely stupid statement to make, but it is important to recognise that other supposedly ion-selective channels (such as, for example, the nicotinic ligand-gated sodium channel at the neuromuscular junction) are barely selective for anything, and allow the passage of whatever cations happen to be around. In contrast to these, sodium is the only thing that passes through Nav1.5. This selectivity is conferred by an extremely narrow (4.6 Å2) pore which is formed by the side chains of four glutamate residues. This molecular site structure is extremely highly conserved and appears to be essential to the functioning of the whole protein, such that minor molecular modifications can completely undermine this selectivity, or control it in a way that permits the conductance of some completely different ions. For example, Heinemann et al (1992) took a rat sodium channel, substituted an alanine for a lysine, and turned it into a calcium channel instead.
Voltage gating occurs by the activity of two gating mechanisms: a voltage-dependent activating gate, conventionally referred to as the "m" gate, and and a time-dependent inactivating gate, usually referred to as the "h" gate. These names come from the original paper by Hodgkin & Huxley (1952), who were trying to express the sodium currents in the giant squid axon mathematically. In the equation they devised, describing sodium conductance, m represented the concentration of hypothetical "activating" molecules that affect the transfer rate for sodium, and h represented "inactivating" molecules. In brief:
In summary, these molecular gate acrobatics explain the different states which the voltage-gated sodium channels can occupy:
The different configurations of the m and h gates produce three distinct states of being:
Why do we care? Well: sodium channel blockers used as Class I antiarrhythmic bind only to the channel in the open or inactivated state, and dissociate from the binding site when the channel is resting during diastole. The kinetics of this relationship are the thing that determines which class of agent the drug falls into:
These are explained to a much better level of detail in the chapter on the ionic basis of spontaneous electrical activity in cardiac muscle. It is relevant to fast voltage gated sodium channels because they are mostly responsible for the "absoluteness" of the absolute period: while the h gate is closed, there is no movement of sodium ions, and no additional stimulus to the cardiac myocyte will promote a depolarisation. In short: