The primary function of the heart is ejection of blood into the vascular system. Individual cardiomyocytes are specialised in the generation of spontaneous activity (automaticity), transmission of the resulting excitable activity and contraction in response to such excitation.
The primary function of the heart is ejection of blood into the vascular system. Individual cardiomyocytes are specialised in the generation of spontaneous activity (automaticity), transmission of the resulting excitable activity and contraction in response to such excitation. Thus:
Atrial and ventricular myocardial cells are capable of both contraction and conduction of action potentials.
– Pacemaker cells, found in the sinoatrial (SA) and atrioventricular (AV) nodes, generate spontaneous cardiac action potentials.
– Conducting cells, known as Purkinje fibres, spread the cardiac action potentials around the ventricles.
Cardiac myocytes share a number of structural features with skeletal muscle:
A striated appearance, owing to organised rows of thick and thin filaments within the sarcoplasm.
A sarcotubular system – ventricular myocytes have both T-tubules and sarcoplasmic reticulum (SR), although they are often less developed than in skeletal muscle.
However, cardiac myocytes also share a number of similarities with smooth muscle:
Involuntary control. Like smooth muscle, the autonomic nervous system (ANS) and endocrine axes modulate the function of cardiac myocytes.
Cells connected by gap junctions. These low-resistance electrical connections allow the rapid conduction of action potentials throughout the myocardium through connexin channels. Thus, the cardiac myocytes contract as a single unit or functional syncytium.
Like the neuronal resting membrane potential (RMP) discussed in Chapter 51, the cardiac myocyte RMP is due to:
A large difference between intracellular and extracellular K+ and Na+ ion concentrations.
The resting cell membrane having a higher permeability to K+ than to Na+.
– In neurons, K+ permeability is predominantly due to membrane K+ leak channels (two-pore-domain K+ channels), which are constitutively open.
– In cardiac myocytes, K+ permeability is due to the presence of inward rectifying K+ channels (Kir channels), which are open at negative membrane potentials, but close with depolarisation.
K+ diffuses down its electrochemical gradient, resulting in the cell interior becoming negatively charged with respect to the cell exterior.
The RMP varies depending on the cardiac region:
SA node, approximately –50 mV, but unstable;
Atrial myocyte, –70 mV;
Purkinje fibre, –90 mV;
Ventricular myocyte, –90 mV.
There are a number of important differences between nerve and cardiac action potentials:
RMP. As discussed above, the RMP of cardiac myocytes varies with cardiac region. Ventricular myocytes and Purkinje fibres have an RMP that is more negative (–90 mV) than the neuronal RMP (–70 mV).
Duration. The nerve action potential is very short (1–2 ms), whilst the cardiac action potential has a much longer duration, depending on myocardial cell type (200–400 ms in ventricular myocytes and Purkinje fibres).
Shape. Morphologically, the nerve action potential is a single spike, whilst the cardiac action potential varies from having a triangular waveform (atrial muscle) to having a long plateau phase (ventricular myocytes and Purkinje fibres).
The role of Ca2+. In cardiac cells, Ca2+ influx prolongs the duration of the action potential, resulting in the characteristic plateau phase of ventricular myocytes. Ca2+ plays no role in the nerve action potential.
The cardiac action potential has five phases (Figure 57.1):
Phase 0, rapid depolarisation.
– The threshold potential for cardiac myocytes is around –65 mV. The threshold potential is reached by the depolarising action of local currents conducted through gap junctions from neighbouring myocytes.
– Stimuli that exceed threshold potential trigger the opening of fast voltage-gated Na+ channels, thereby increasing membrane Na+ permeability.
– The resultant increased Na+ influx causes a further membrane depolarisation, which triggers further opening of voltage-gated Na+ channels; a positive-feedback loop is created.
– The end result is rapid depolarisation to approximately +20 mV.
Phase 1, early rapid repolarisation. Following the membrane depolarisation of phase 0:
– Voltage-gated Na+ channels inactivate, resulting in a rapid decrease in the membrane Na+ permeability.
– Fast voltage-gated K+ channels transiently open, resulting in a transient outward K+ current Ito (Figure 57.2).
The overall effect is a brief phase of repolarisation.
Phase 2, plateau. Membrane depolarisation is maintained for a prolonged period (around 200 ms) through a balance of inward and outward currents:
– Inward current: voltage-gated L-type Ca2+ channels slowly open following membrane depolarisation. Ca2+ ions flow down their concentration gradient from the extracellular fluid (ECF), where the ionised Ca2+ concentration is around 1.2 mmol/L, to the intracellular fluid (ICF), which has a considerably lower ionised Ca2+ concentration (around 500 nmol/L).
– Outward current: as discussed above, Kir channels are predominantly responsible for generating the RMP, but close following membrane depolarisation. At the same time, membrane depolarisation causes slow delayed rectifier K+ channels to open.
Overall, there is a net inward current that maintains the plateau.
Phase 4, electrical diastole. During this phase, the membrane is maintained at RMP due to K+ efflux through Kir channels. There is also a correction of the small net fluxes of Na+, K+ and Ca2+ that took place during the action potential through Na+/K+-ATPase and Na+/Ca2+-exchanger activity.
In summary (Figure 57.2):
Phase 0 – a brief, rapid increase in Na+ conductance results in rapid depolarisation.
Phase 1 – K+ conductance increases transiently.
Phase 2 – the increase in Ca+ conductance results in an inward Ca2+ current, which opposes the tendency of the outward K+ current to restore the membrane potential, resulting in the action potential plateau.
Phase 3 – a decrease in Ca2+ conductance and a progressive increase in K+ conductance results in membrane repolarisation.
Phase 4 – Ca2+, Na+ and K+ conductance have returned to resting levels, with K+ conductance exceeding Ca2+ and Na+ conductance, resulting in the RMP.
Phases 0 and 1 have a total duration of 1–2 ms, similar to that of the nerve action potential. The summed activity of phase 0 and 1 across the septum and ventricular wall corresponds to the QRS complex of the electrocardiogram (ECG).
Phase 2 lasts for around 200 ms and corresponds to the ST-segment of the ECG.
Phase 3 takes around 50 ms, and corresponds to the T-wave of the ECG.
The duration of the action potential decreases with increasing HR: at a rate of 200 bpm, the action potential lasts for only 150 ms. This is why QT intervals must be corrected (QTc) to make values comparable across a range of HRs.
Figure 57.1 The phases of the cardiac action potential.
Figure 57.2 Changes in membrane permeability to ions during the cardiac action potential.
What are the refractory periods of the cardiac action potential?
The absolute refractory period (ARP), where a further action potential cannot be initiated, no matter how large a stimulus is applied. Following membrane depolarisation, the fast voltage-gated Na+ channels become inactivated. Inactivated Na+ channels cannot return to their resting state until membrane repolarisation has occurred. The prolonged plateau phase of the cardiac action potential means that the ARP is 200 ms, which is considerably longer than that of the nerve action potential. The long ARP of cardiac muscle means that further action potentials cannot be triggered until muscle contraction is nearly complete (Figure 57.3b). A short ARP could potentially lead to tetany of the cardiac muscle, which would be incompatible with diastolic filling.
The relative refractory period (RRP), when a further action potential can be initiated, but it requires a greater stimulus than normal.
(a) The absolute refractory period (ARP) and relative refractory period (RRP) of the cardiac action potential.
(b) Relationship between the cardiac action potential and the contractile response of cardiac muscle.
The Singh–Vaughan Williams classification (Table 57.1) categorises antiarrhythmic drugs into four classes on the basis of their ionic mechanism. Later, Class V was added to include antiarrhythmic drugs with mechanisms dissimilar to the other four classes. However, few antiarrhythmic drugs are specific to one class. For example, flecainide (Class 1C) also blocks K+ channels, amiodarone (Class III) also blocks Na+ and Ca2+ channels and sotalol (Class III) is also a β-blocker. It is also important to note that relatively few drugs are effective in the treatment of ventricular fibrillation; cardioversion is therefore indicated.