24A12: Exam Report

(a) Describe the action potential of the cardiac pacemaker cells including the ionic events (60%).
(b) Explain how excitation then propagates through the conducting pathway of the heart, including mechanisms to prevent abnormal conduction (40%).

69% of candidates passed this question.

  • (a) A detailed description of the ionic events of the phases of the sino-atrial node AP was expected. A diagram of the sino-atrial node potential which included the phases and labelled x and y axis was helpful in this description. Some comparison with other cardiac action potentials added depth to answers, as did a brief description of the inflences on the action potential such as the autonomic nervous system.
  • (b) This section required a detailed explanation of impulse propagation both between cardiac myocytes and across the myocardium. Safety mechanisms to be mentioned included anatomical insulation, refractory periods and rate.

G2i / 24A12:
(a) Describe the action potential of the cardiac pacemaker cells including the ionic events (60%).
(b) Explain how excitation then propagates through the conducting pathway of the heart, including mechanisms to prevent abnormal conduction (40%).

Structure

  • Cardiac pacemaker cells are specialized cardiac myocytes, and exhibit automaticity ie the ability of the heart to initiate its own beat, without neural input. They also exhibit intrinsic rhythmicity – regularity at which a heartbeat is initiated.
  • Pacemaker cells produce slow response action potentials, and include SA and AV nodal cell fibres.
  • Fast response cardiac action potentials include atrial and ventricular myocytes; Purkinje fibres can exhibit both fast and slow responses.
  • Cardiac action potentials are elicited by local ionic currents, via changes in the cell membrane permeability to Na+, K+ and Ca++.
  • Pacemaker cells have a “wandering” resting potential (mV) which is “less negative”, reaching threshold for depolarization more readily vs a fast AP (approx. -65 to -60 mV, with a threshold of -40mV)
  • Duration: 150- 200 m/s
  • Absolute refractory period (ARP): from phase 0 to 2/3 of repolarization phase 3. A new action potential cannot be generated. This safety mechanism prevents tetany of cardiac muscle.
  • Relative refractory period (RRP): A new action potential is possible, only if a supra maximal stimulus is applied to reach threshold for depolarization. RRP accounts for last 1/3 of repolarization stage and phase 4.

Phases

0 – Depolarization

Depolarization once “wandering” threshold reached. Opening VG T – type (initially around -50mV) and L – type Ca++ channels (around -30 mV) increases conductance and entry of Ca++ into cell (gCa). Influx of Ca++ ions enhances membrane depolarization.

Smaller peak just over 0mV, and less steep upstroke vs Ph 0 of fast AP’s (which instead require fast VG Na+ channel opening and Na+ influx).

1 – Phase

No phase 1 in comparison to fast myocyte AP; plateau phase not sustained

2 – Phase

No phase 2 in comparison to fast myocyte AP; plateau phase not sustained

3 – Repolarization phase

Increased K+ conductance (gK) via K+ rectifier channels, where K+ efflux out of cell returns transmembrane potential to below threshold. This is more gradual compared to a fast AP repolarization.

4 – “Pacemaker potential”

Pacemaker potential found in nodal cells exhibits slow depolarization; gradual progression at a steady state until threshold potential (-40mV) is reached and an action potential is generated. This “unstable resting potential” tends to lie between -65 to -60 mV at the start of ph 4.

This is distinct from the “constant” resting membrane potential of non nodal cells, typically set at -90mV (atrial and ventricular myocytes).

Historically the pacemaker potential was called the “funny” sodium current (If), or “hyperpolarization- induced inward current”

This is maintained by:

  • Na+ channels allowing influx of cations (different to fast VG Na+). The more negative trans membrane potential is at the end of repolarization, the greater the activation of the If.
  • Opening of L-type Ca++ channels at -50mV once more brings pacemaker potential towards threshold (more positive mV) – ICa
  • An outward K+ current (Ik) – continues beyond phase 3, but progressively slower by end of phase 4 (to counterbalance net influx from If and ICa.).

           

Nodal cells lack Inward rectifier K+ channels; thus have a lower conductance of K+ (in comparison to fast AP’s (-65mv vs -90 mV)).

During phase 4, a supra maximal stimulus can elicit an action potential ie within the RRP.

Graph of cardiac action potential phases and ion movement.

B: Impulse propagation between myocytes

Conduction in cardiac fibres depends on local circuit currents, and the propagation of an action potential is similar to that of nerve and skeletal muscle fibres.

Cardiac myocytes have both electrical and mechanical connections. Structurally, end to end connections between myocytes via intercalated discs allow the coordinated contraction as a functional syncytium. Adjacent to the discs are gap junctions which allow an action potential to pass from one myocyte to the next.

Current flows from regions of higher (positive) potential to those of lower (negative) potential; this ensures uni directional spread of a signal.

Diagram of myocardial fiber depolarization and repolarization.

Normal conduction system of the heart

  • SA node contains a collection of specialized pacemaker cells, located at the junction between the SVC and upper wall of the right atrium.
  • SA node initiates an impulse and propagates signal (conduction velocity ~ 1 m/s) across the atria to AV node via inter nodal pathways.
  • 3 inter nodal tracts known:
    • Anterior (Bachman pathway)
    • Middle (Wenckebach pathway)
    • Posterior (Thorel pathway).
  • Bachman’s pathway also conducts impulses from SAN to the left atrium (Anterior interatrial myocardial band).
  • AV node is situated posteriorly on the right side of the inter atrial septum, measuring 22 l x 10 w x 3 depth mm. Surrounding structures: ostium of the coronary sinus, Tendon of Todaro and the tricuspid valve. This fibrous structure is the only conducting pathway between atria and ventricles, and can be split into 3 regions (AN, N and HN region).
  • The AVN provides a delay to impulses (~ 120 m/s) sent to the Bundle of His, to ensure enough time for atrial emptying and passive filling of ventricles; this matches the P-R interval seen on ECG. Bundle of His is located ~1cm inferiorly to the AVN, before splitting into Left and Right bundle branches.
  • Signal travels to the Bundle of His and down Purkinje fibres (located in sub endocardium) within the inter ventricular septum; they are a specialized network of myocytes that conduct electrical impulses to the ventricles.
  • The Left bundle branch is thicker and perforates the inter ventricular septum (at 90o) to supply the left ventricle, and once located within subendocardial surface splits into an Anterior and Posterior division.
  • The Right bundle branch is a direct continuation of the Bundle of His, and supplies the right ventricle.
  • The first part of the ventricle to be depolarized is the apex, with excitation spreading from the endocardium to epicardial surface; by activating the apices first, and basal segments last, this aids ejection of blood outwards towards outflow tracts.
Heart conduction pathway diagram components labeled.
  • Conduction abnormalities aka brady – and tachy- arrhythmias, can be propagated by structural and metabolic derangements, as well as drugs, 
  • Slow response action potentials can be detected from abnormal myocardial cells that have been partially depolarized (eg ischaemic tissue with high EC K+ concentration); this is known as “enhanced automaticity” where the resting potential of contractile tissue losses its stability and may reach threshold for depolarization before the SA node does.
  • AV conduction is regulated by the ANS (Noradrenaline via SNS and ACh via PSNS).
    • Cardiac sympathetic fibres facilitate normal conduction by decreasing AV conduction velocity and enhancing rhythmicity of latent pacemaker cells (via NA release to raise pacemaker potential/ ph 4).
  • Excessive vagal activity may cause some or all impulses arriving from the atria to be blocked at the AVN, causing 3rd degree/ complete HB.
    • 1st and 2nd degree HB are frequently caused by inflammatory processed (eg rheumatic fever), drugs (eg CCBs) and rapid atrial rates (eg SVTs).
    • 3rd degree HB often caused by degenerative processes, including post ischaemic myocardial changes.

Safety mechanisms to prevent abnormal conduction

1. Anatomical insulation

  1. Conduction of impulses between SA and AV node have both fast and slow pathways, which increases chances of re-entrant circuits within the AV node. Cells within the inferior portion of the AVN (N region) serve as a subsidiary pacemaker ie supplement main pacemaker function of the SA node.
    1. Functionally, support the delay between atrial and ventricular excitation permits optimal ventricular filling during atrial contraction. As the repetition rate of atrial depolarizations is increased, conduction through the AV junction slows down. When abnormally prolonged AV conduction occurs, termed as “first-degree AV block”.
    2. Retrograde conduction can occur via AV node, however propagation time is significantly slower and the impulse tends to be blocked at lower repetition rates.
    3. If there is decreased or no conduction via the AVN (eg excess vagal tone), pacemaker cells within the Bundle of His and Purkinje system can generate action potentials at slower rate of 15- 40 bpm ie a ventricular escape rhythm.

2. Refractory periods

Absolute refractory periods span the majority of an action potential (> 2/3’s of total AP duration). This is a safety mechanism to avoid cardiac muscle summation of contractions, also known as tetany.

If a supra maximal stimulus were to occur during the RRP, the contraction produced would be weaker (due to a slower depolarization rate and overall amplitude of Ph 0 reached).

So, even if a new AP were triggered during the RRP, it is not possible to extend it onto the ARP, and so tetanic contraction in cardiac muscle is not possible (unlike with skeletal muscle).

Accessory pathways may bypass this safety mechanism by allowing 2 distinct conduction pathways to work concurrently, and being potentially exposed when premature atrial impulses arrive within one circuit’s RRP.

This is known as a “Atrioventricular nodal re-entrant tachycardia” where an action potential is followed by a refractory period, as seen with WPW syndrome via Bundle of Kent (not the AV node).

3. Rate

SA node has the fastest firing rate (100- 110 impulses/ min), compared to Purkinje fibres (15- 30 impulses/min), and so becomes the dominant pacemaker with highest rhythmicity (able to suppress the automaticity of other loci in the heart).

  1. Discharge frequency of pacemaker cells may be altered if there is a change in:
    1. Rate of depolarization ie how “steep” phase 4/ pacemaker potential is, and how quickly threshold potential will be reached for depolarization.
      Increased sympathetic activity via NA release increases HR by increasing the slope of the pacemaker potential (via B- adrenergic stimulation increasing all 3 ionic currents (If/ ICa / Ik) involved in SA node automaticity, particularly calcium permeability).
    2. Maximal diastolic potential ie an increase in the maximum negativity at the end of repolarization. The more “negative” transmembrane potential is with hyperpolarization, the longer it takes to reach threshold once again from pacemaker potential ie reduction in frequency of AP firing.
      Increased vagal activity (via release of ACh onto specific K+ channels with cholinergic receptors- increases K+ permeability of the SA node) diminishes rate via hyperpolarization of the pacemaker cell membrane.
      Nodal cells are rich in cholinesterases to ensure vagal activity displays very short latency (~ 50 -100 ms).
Graphs showing heart rate changes with nervous stimulation.

“Overdrive Suppression” Phenomenon

Where a period of excitation at high frequency depresses the automaticity of pacemaker cells (via hyper polarization).

Why: As an excess of Na+ influx occurs from rapid depolarization, the Na+/ K+ / ATPase pump keeps up with this activity (pumping 3 Na+ out/ 2 K+ in), and causes an overall loss of cations to the EC space ie hyper polarizes cell membrance (more negative mV); this causes a slow diastolic depolarization and is seen as a transient suppression of the pacemaker’s intrinsic automaticity

References

  • Diagrams – Chambers + Power and Kam
  • Ref – Pappano/ Chambers / Peck and Hill

Author: Ines Vaz