Electrophysiology
Of Cardiac Muscle And Origin Of The
Heart Beat
An action potential (AP) is the
transient depolarization of a cell as a result of activity of ion channels. The
cardiac AP is considerably longer than those of nerve or skeletal muscle (∼300
vs ∼2
ms). This is due to a plateau
phase in cardiac muscle, lasting for 200–300
ms.
(Figure 11a)
At rest, the ventricular cell membrane is most permeable to K+
and the resting membrane potential (RMP)
is therefore close to the K+ equilibrium potential (EK), ∼–90
mV (see Chapter 10). An AP is initiated when the membrane is depolarized to the
threshold potential (∼−65
mV). This occurs due to transmission of a depolarizing current from an adjacent
activated cell through gap junctions (see Chapter 2). At threshold,
sufficient voltage-gated Na+ channels are activated to initiate a
self-regenerating process – the inward current caused by entry of Na+
(INa) through these channels causes further depolarization,
which activates more Na+ channels, and so on. The outcome is a very large and
fast INa, and therefore a very rapid AP upstroke (phase 0; ∼500
V/s).
Activation of Na+ channels during phase 0 means that the Na+
permeability is now much greater than that for K+, and so the membrane
potential moves towards the Na+ equilibrium potential (ENa,
∼+65
mV) (see Chapter 10). It does not reach ENa because the Na+ channels
rapidly inactivate as the potential nears +40 mV (see Chapter 10); this,
and activation of a transient outward K+ current, can lead to a
rapid decline in potential, leaving a spike (phase 1), best seen in
Purkinje fibres (Figure 11d). The inactivated Na+ channels cannot be
reactivated until the potential returns to less than −60 mV, so another AP cannot be initiated
until the cell repolarizes (refractory period). The refractory period
therefore lasts as long as the plateau and contraction (Figure 11a), so unlike
skeletal muscle, cardiac muscle cannot be tetanized.
By the end of the upstroke all Na+ channels are inactivated, and in
skeletal muscle the cell would now repolarize. In cardiac muscle, however, the
potential remains close to 0 mV for ∼250 ms. This plateau phase is
due to opening of voltage-gated (L-type) Ca2+ channels,
which activate relatively slowly when the membrane potential becomes more
positive than ∼−35 mV. The resultant Ca2+
current (slow inward or ISI) is sufficient to slow
repolarization until the potential falls to ∼−20
mV. The length of the plateau is related to slow inactivation of Ca2+
channels and the additional Na+ inward current provided by the Na+–Ca2+
exchanger (see below). Ca2+ entry during the plateau is vital for
cardiac muscle contraction (see
Chapter 12).
By the end of the plateau the membrane potential is sufficiently negative
to activate delayed rectifier K+ channels, and the associated outward K+
current (IK) therefore promotes rapid repolarization. As the
membrane potential returns to resting levels (phase 4), IK
slowly inactivates again. Factors that influence IK will
affect the rate of repolarization, and hence the AP length (see Chapter 51),
and mutations in the underlying channels cause long QT syndrome (see Chapter
55).
Role of Na+–Ca2+ exchange
The Na+–Ca2+ exchanger (NCX) exchanges three Na+
for one Ca2+, and is thus electrogenic (see Chapter 10). In the
early plateau, when membrane potential is most positive, the NCX may reverse
and contribute to inward current and movement of Ca2+. As the
plateau decays and becomes more negative NCX returns to its usual function of
expelling Ca2+ from the cell in exchange for Na+, which is
potentiated by the high cytosolic [Ca2+]. This influx of Na+ ions
causes an inward current (INCX) that slows repolarization and
lengthens the plateau.
Sinoatrial node
The sinoatrial node (SAN) is the origin of the heart beat, and its
AP differs from that of the ventricle (Figure 11b). The resting potential
(phase 4) exhibits a slow depolarization, and the upstroke (phase 0) is much
slower. The latter is because there are no functional Na+ channels, and the
upstroke is due instead to activation of slow L-type Ca2+ channels.
The slow upstroke leads to slower conduction between cells (see Chapter 13).
This is of particular importance in the atrioventricular node (AVN),
which has a similar AP to the SAN.
The SAN resting potential slowly depolarizes from ∼−60 mV to a threshold of ∼−40
mV, at which point L-type channels activate and an AP is initiated; the
threshold is more positive because of substitution of L-type for Na+ channels.
The rate of decay deter-mines how long it takes for threshold to be reached,
and therefore the heart rate. The resting potential is therefore commonly
called the pacemaker potential. As for ventricular cells, repolarization
of the AP in SAN involves activation of IK, which then slowly
inactivates. In addition, there are two inward currents, Ib
and If (‘funny’), mostly due to inward
movement of Na+. Ib is stable, and present
in other cardiac cells, but If is specific to nodal
cells, and activated at the end of repolarization by negative potentials
(Figure 11b). The combination of inward current from If plus
Ib and decay in IK causes the slow
depolarization of the pacemaker potential. As this approaches threshold,
another type of voltage- gated Ca2+ channel (transient, T-type) is
activated, which contributes to the depolarization and the early part of the
upstroke.
Factors influencing IK, Ib,
or If thus alter the slope of the pace- maker and so
heart rate, and are called chronotropic agents. The sympathetic
neurotransmitter noradrenaline increases heart rate by increasing the size of If.
It also reduces AP length by increasing the rate of Ca2+ entry and
hence the slope of the upstroke. The parasympathetic transmitter acetylcholine
reduces the slope of the pacemaker potential and causes a small
hyperpolarization, both of which increase the time required to reach threshold
and reduce heart rate (Figure 11c).
Other regions of the heart (Figure 11d)
Atrial muscle has a similar AP to ventricular muscle, although the shape
is more triangular. Purkinje fibres in the conduction system have a
prominent phase 1, reflecting a greater INa (due to
their large size); the latter causes a more rapid upstroke, and faster conduction.
APs in the AVN are similar to those of the SAN, although the rate of decay of
the resting potential is slower. The resting potential of the bundle of His and
Purkinje system may also exhibit an even slower rate of decay (due to decay of IK).
All of these could therefore act as pacemakers, but the SAN is normally faster
and. This is called dominance or overdrive suppression.
