The cardiac action potential is a brief change in voltage (membrane potential) across the cell

membrane of heart cells.[1] This is caused by the movement of charged atoms (called ions) between
the inside and outside of the cell, through proteins called ion channels. The cardiac action potential
differs from action potentials found in other types of electrically excitable cells, such as nerves.
Action potentials also vary within the heart; this is due to the presence of different ion channels in
different cells (see below).
Unlike the action potential in skeletal muscle cells, the cardiac action potential is not initiated by
nervous activity. Instead, it arises from a group of specialized cells, that have automatic action
potential generation. In healthy hearts, these cells are found in the right atrium and are called
the sinoatrial node (SAN; see below for more details). They produce roughly 60-100 action potentials
every minute. This action potential passes along the cell membrane causing the cell to contract,
therefore the activity of the SAN results in a resting heart rate of roughly 60-100 beats per minute. All
cardiac muscle cells are electrically linked to one another, by structures known as gap junctions (see
below) which allow the action potential to pass from one cell to the next.[2] This means that all atrial
cells can contract together, and then all ventricular cells.
Rate dependence of the action potential is a fundamental property of cardiac cells and alterations
can lead to severe cardiac diseases including cardiac arrhythmia and sometimes sudden
death.[3] Action potential activity within the heart can be recorded to produce an electrocardiogram
(ECG). This is a series of upward and downward spikes (labelled P, Q, R, S and T) that represent
the depolarization (voltage becoming more positive) and repolarization (voltage becoming more
negative) of the action potential in the atria and ventricles[4](see electrocardiography for more
details).

Contents
[hide]

 1Overview
 2Phases of the cardiac action potential
o 2.1Phase 4
o 2.2Phase 0
o 2.3Phase 1
o 2.4Phase 2
o 2.5Phase 3
 3Refractory period
 4Gap junctions
 5Channels
o 5.1Hyperpolarisation activated cyclic nucleotide gated (HCN) channels
o 5.2The fast Na+ channel
o 5.3Potassium channels
o 5.4Calcium channels
 6Autorhythmicity
o 6.1Regulation by the autonomic nervous system
 7See also
 8References
 9Bibliography
 10External links

Overview[edit]
Similar to skeletal muscle, the resting membrane Figure 1: Intra- and
potential (voltage when the cell is not electrically extracellular ionconcentrations (mmol/L)
excited) of ventricular cells, is around -90 Element Ion Extracellular Intracellular Ratio
millivolts (mV; 1mV=0.001V) i.e. the inside of the
membrane is more negative than the outside. Sodium Na+ 135 - 145 10 14:1
The main ions found outside the cell at rest are: Potassium K+ 3.5 - 5.0 155 1:30
sodium (Na+), and chloride (Cl−), whereas inside Chloride Cl− 95 - 110 10 - 20 4:1
the cell it is mainly potassium (K+).[6]
2x
The action potential begins with the voltage Calcium Ca2+ 2 10−4
104:1
becoming more positive; this is known Although intracellular Ca2+ content is about 2 mM, most of
as depolarization and is mainly due to the this is bound or sequestered in intracellular organelles
opening of sodium channels that allow Na+ to (mitochondria and sarcoplasmic reticulum).[5]
flow into the cell. After a delay (known as the
absolute refractory period; see below), termination of the action potential then occurs, as potassium
channels open, allowing K+ to leave the cell and causing the membrane potential to return to
negative, this is known as repolarization. Another important ion is calcium (Ca2+), which can be found
outside of the cell as well as inside the cell, in a calcium store known as the sarcoplasmic reticulum
(SR). Release of Ca2+ from the SR, via a process called calcium-induced calcium release, is vital for
the plateau phase of the action potential (see phase 2, below) and is a fundamental step in cardiac
excitation-contraction coupling.[7]
There are important physiological differences between the cells that spontaneously generate the
action potential (pacemaker cells; e.g. SAN) and those that simply conduct it (non-pacemaker cells;
e.g. ventricular myocytes). The specific differences in the types of ion channels expressed and
mechanisms by which they are activated results in differences in the configuration of the action
potential waveform, as shown in figure 2.

Phases of the cardiac action potential[edit]

Action potentials recorded from sheep atrial and ventricular cardiomyocytes with phases shown. Ion currents
approximate to ventricular action potential.
The standard model used to understand the cardiac action potential is that of the ventricular
myocyte. Outlined below are the five phases of the ventricular myocyte action potential, with
reference also to the SAN action potential.

Figure 2a: Ventricular action potential (left) and sinoatrial node action potential (right) waveforms. The main
ionic currents responsible for the phases are below (upwards deflections represent ions flowing out of cell,
downwards deflection represents inward current).

Phase 4[edit]
In the ventricular myocyte, phase 4 occurs when the cell is at rest, in a period known as diastole. In
the standard non-pacemaker cell the voltage during this phase is more or less constant, at roughly -
90mV.[8]The resting membrane potential results from the flux of ions having flowed into the cell (e.g.
sodium and calcium) and the ions having flowed out of the cell (e.g. potassium, chloride and
bicarbonate) being perfectly balanced.
The leakage of these ions, across the membrane is maintained by the activity of pumps which serve
to keep the intracellular concentration more or less constant, so for example, the sodium
(Na+) and potassium (K+) ions are maintained by the sodium-potassium pump which uses energy (in
the form of adenosine triphosphate (ATP)) to move three Na+ out of the cell and two K+ into the cell.
Another example is the sodium-calcium exchanger which, removes one Ca2+ from the cell for three
Na+ into the cell.[9]
During this phase the membrane is most permeable to K+, which can travel into or out of cell through
leak channels, including the inwardly rectifying potassium channel.[10] Therefore, the resting
membrane potential is mainly determined by K+ equilibrium potential and can be calculated using
the Goldman-Hodgkin-Katz voltage equation.
However, pacemaker cells are never at rest. In these cells, phase 4 is also known as the pacemaker
potential. During this phase, the membrane potential slowly becomes more positive, until it reaches
a set value (around -40mV; known as the threshold potential) or until it is depolarized by another
action potential, coming from a neighboring cell.
The pacemaker potential is thought to be due to a group of channels, referred to as HCN channels
(Hyperpolarisation-activated cyclic nucleotide-gated). These channels open at very negative
voltages (i.e. immediately after phase 3 of the previous action potential; see below) and allow the
passage of both K+and Na+ into the cell. Due to their unusual property of being activated by very
negative membrane potentials, the movement of ions through the HCN channels is referred to as
the funny current (see below).[11]
Another theory regarding the pacemaker potential is the ‘calcium clock’. Here, calcium is released
from the sarcoplasmic reticulum, within the cell. This calcium then increases activation of
the sodium-calcium exchanger resulting in the increase in membrane potential (as a +3 charge is
being brought into the cell (by the 3Na+) but only a +2 charge is leaving the cell (by the Ca2+)
therefore there is a net charge of +1 entering the cell). This calcium is then pumped back into the cell
and back into the SR via calcium pumps (including the SERCA).[12]

Phase 0[edit]
This phase consists of a rapid, positive change in voltage across the cell membrane (depolarization)
lasting less than 2ms, in ventricular cells and 10/20ms in SAN cells.[13] This occurs due to a net flow
of positive charge into the cell.
In non-pacemaker cells (i.e. ventricular cells) this is produced predominantly by the activation
of Na+ channels, which increases the membrane conductance (flow) of Na+ (gNa). These channels are
activated when an action potential arrives from a neighbouring cell, through gap junctions. When this
happens, the voltage within the cell increases slightly. If this increased voltage reaches a certain
value (threshold potential; ~-70mV) it causes the Na + channels to open. This produces a larger
influx of sodium into the cell, rapidly increasing the voltage further (to ~ +50mV;[6] i.e. towards the
Na+ equilibrium potential). However, if the initial stimulus is not strong enough, and the threshold
potential is not reached, the rapid sodium channels will not activate and an action potential will not
be produced, this is known as the All-or-none law .[14][15] The slope of phase 0 on the action potential
waveform (see figure 2) represents the maximum rate of voltage change, of the cardiac action
potential and is known as dV/dtmax.
In pacemaker cells (e.g. sinoatrial node cells), however, the increase in membrane voltage is mainly
due to activation of L-type calcium channels. These channels are also activated by an increase in
voltage, however this time it is either due to the pacemaker potential (phase 4) or an oncoming
action potential. The L-type calcium channels activate towards the end of the pacemaker
potential (and therefore contribute to the latter stages of the pacemaker potential). The L-type
calcium channels activate slower than the sodium channels, in the ventricular cell, therefore, the
depolarization slope in the pacemaker action potential waveform is less steep than that in the non-
pacemaker action potential waveform.[8][16]

Phase 1[edit]
This phase begins with the rapid inactivation of the Na + channels by the inner gate (inactivation
gate), reducing the movement of sodium into the cell. At the same time potassium channels (called
Ito1) open and close rapidly, allowing for a brief flow of potassium ions out of the cell, making the
membrane potential slightly more negative. This is referred to as a ‘notch’ on the action potential
waveform.[8]
There is no obvious phase 1 present in pacemaker cells.

Phase 2[edit]
This phase is also known as the "plateau" phase due to the membrane potential remaining almost
constant, as the membrane very, very slowly begins to repolarize. This is due to the near balance of
charge moving into and out of the cell. During this phase delayed rectifier potassium channels allow
potassium to leave the cell whilst L-type calcium channels (activated by the flow of sodium during
phase 0), allow the movement of calcium into the cell. This calcium, binds to and opens more
calcium channels (called ryanodine receptors) located on the sarcoplasmic reticulum within the cell,
allowing the flow of calcium out of the SR. This calcium is responsible for contraction of the heart.
Not only that, but it also activates chloride channels called Ito2, which allow Cl− to enter the cell.
Together the movement of both Ca2+ and Cl− oppose the voltage change caused by K+. As well as
this the increased calcium concentration increases the activity of the sodium-calcium exchanger, and
the increase in sodium entering the cell increases activity of the sodium-potassium pump. The
movement of all of these ions results in the membrane potential remaining relatively
constant.[17][8] This phase is responsible for the large duration of the action potential and is important
in preventing irregular heartbeat (cardiac arrhythmia).
There is no plateau phase present in pacemaker action potentials.

Phase 3[edit]
During phase 3 (the "rapid repolarization" phase) of the action potential, the L-
type Ca2+ channels close, while the slow delayed rectifier (IKs) K+ channels remain open as more
potassium leak channels open. This ensures a net outward positive current, corresponding to
negative change in membrane potential, thus allowing more types of K+ channels to open. These are
primarily the rapid delayed rectifier K+ channels (IKr) and the inwardly rectifying K+ current, IK1. This
net outward, positive current (equal to loss of positive charge from the cell) causes the cell to
repolarize. The delayed rectifier K+ channels close when the membrane potential is restored to about
-85 to -90 mV, while IK1 remains conducting throughout phase 4, which helps to set the resting
membrane potential[18]
Ionic pumps as discussed above, like the sodium-calcium exchanger and the sodium-potassium
pump restore ion concentrations back to balanced states pre-action potential. This means that the
intracellular calcium is pumped out, which was responsible for cardiac myocyte contraction. Once
this is lost the contraction stops and myocytic cells relax, which in turn relaxes the heart muscle.
During this phase, the action potential fatefully commits to repolarisation. This begins with the
closing of the L-type Ca2+channels, while the K+ channels (from phase 2) remain open. The main
potassium channels involved in repolarization are the delayed rectifiers (IKr) and (IKs) as well as
the inward rectifier (IK1). Overall there is a net outward positive current, that produces negative
change in membrane potential.[19] The delayed rectifier channels close when the membrane potential
is restored to resting potential, whereas the inward rectifier channels and the ion pumps remain
active throughout phase 4, resetting the resting ion concentrations. This means that the calcium
used for muscle contraction, is pumped out of the cell, resulting in muscle relaxation.
In the sinoatrial node, this phase is also due to the closure of the L-type calcium channels,
preventing inward flux of Ca2+ and the opening of the rapid delayed rectifier potassium channels
(IKr).[20]

Refractory period[edit]
Cardiac cells have two refractory periods, the first from the beginning of phase 0 until part way
through phase 3; this is known as the absolute refractory period during which it is impossible for the
cell to produce another action potential. This is immediately followed, until the end of phase 3, by a
relative refractory period, during which a stronger-than-usual stimulus is required to produce another
action potential.[21][22]
These two refractory periods are caused by changes in the states of sodium and potassium
channels. The rapid depolarization of the cell, during phase 0, causes the membrane potential to
approach sodium’s equilibrium potential (i.e. the membrane potential at which sodium is no longer
drawn into or out of the cell). As the membrane potential becomes more positive, the sodium
channels then close and lock, this is known as the "inactivated" state. During this state the channels
cannot be opened regardless of the strength of the excitatory stimulus—this gives rise to the
absolute refractory period. The relative refractory period is due to the leaking of potassium ions,
which makes the membrane potential more negative (i.e. it is hyperpolarised), this resets the sodium
channels; opening the inactivation gate, but still leaving the channel closed. This means that it is
possible to initiate an action potential, but a stronger stimulus than normal is required.[23]

Gap junctions[edit]
Gap junctions allow the action potential to be transferred from one cell to the next (they are said
to electrically couple neighbouring cardiac cells). They are made from the connexin family of
proteins, that form a pore through which ions (including Na+, Ca2+ and K+) can pass. As potassium is
highest within the cell, it is mainly potassium that passes through. This increased potassium in the
neighbour cell causes the membrane potential to increase slightly, activating the sodium channels
and initiating an action potential in this cell. (A brief chemical gradient driven efflux of Na+ through
the connexon at peak depolarization causes the conduction of cell to cell depolarization, not
potassium.)[24] These connections allow for the rapid conduction of the action potential throughout the
heart and are responsible for allowing all of the cells in the atria to contract together as well as all of
the cells in the ventricles.[25] Uncoordinated contraction of heart muscles is the basis for arrhythmia
and heart failure.[26]

Figure 3: Major currents during the cardiac ventricular action potential[27]

Current (I) α subunit protein α subunit gene Phase / role
Na+ INa NaV1.5 SCN5A[28] 0
Ca2+ ICa(L) CaV1.2 CACNA1C[29] 0-2
K +
Ito1 KV4.2/4.3 KCND2/KCND3 1, notch
K+ IKs KV7.1 KCNQ1 2,3
K +
IKr KV11.1 (hERG) KCNH2 3
K+ IK1 Kir2.1/2.2/2.3 KCNJ2/KCNJ12/KCNJ4 3,4
Na+, Ca2+ INaCa 3Na+-1Ca2+-exchanger NCX1 (SLC8A1) ion homeostasis
Na , K + +
INaK 3Na -2K -ATPase
+ +
ATP1A ion homeostasis
Ca2+ IpCa Ca2+-transporting ATPase ATP1B ion homeostasis

Channels[edit]
Ion channels are proteins, that change shape in response to different stimuli to either allow or
prevent the movement of specific ions across a membrane (they are said to be selectively
permeable). Stimuli, which can either come from outside the cell or from within the cell, can include
the binding of a specific molecule to a receptor on the channel (also known as ligand-gated ion
channels) or a change in membrane potential around the channel, detected by a sensor (also known
as voltage-gated ion channels) and can act to open or close the channel. The pore formed by an ion
channel is aqueous (water filled) and allows the ion to rapidly travel across the membrane.[30] Ion
channels can be selective for specific ions, so there are Na+, K+, Ca2+, and Cl− specific channels.
They can also be specific for a certain charge of ions (i.e. positive or negative).[31]
Each channel is coded by a set of DNA instructions that tell the cell how to make it. These
instructions are known as a gene. Figure 3 shows the important ion channels involved in the cardiac
action potential, the current (ions) that flows through the channels, their main protein subunits
(building blocks of the channel), some of their controlling genes that code for their structure and the
phases they are active during the cardiac action potential. Some of the most important ion channels
involved in the cardiac action potential are described briefly below.

Hyperpolarisation activated cyclic nucleotide gated (HCN)

channels[edit]
Located mainly in pacemaker cells, these channels become active at very negative membrane
potentials and allow for the passage of both Na+ and K+ into the cell (this movement is known as a
funny current, If). These poorly selective, cation (positively charged ions) channels conduct more
current as the membrane potential becomes more negative (hyperpolarised). The activity of these
channels in the SAN cells causes the membrane potential to depolarise slowly and so they are
thought to be responsible for the pacemaker potential. Sympathetic nerves directly affect these
channels, resulting in an increased heart rate (see below). [32][11]

The fast Na+ channel[edit]

Main article: Sodium channel
These sodium channels are voltage-dependent, opening rapidly due to depolarization of the
membrane, which usually occurs from neighboring cells, through gap junctions. They allow for a
rapid flow of sodium into the cell, depolarizing the membrane completely and initiating an action
potential. As the membrane potential increases, these channels then close and lock (become
inactive). Due to the rapid influx sodium ions (steep phase 0 in action potential waveform) activation
and inactivation of these channels happens almost at exactly the same time. During the inactivation
state, Na+ cannot pass through (absolute refractory period). However they begin to recover from
inactivation as the membrane potential becomes more negative (relative refractory period).

Potassium channels[edit]
Main article: Potassium channel
The two main types of K+ channels in cardiac cells are inward rectifiers and voltage-gated potassium
channels.
Inwardly rectifying potassium channels (Kir) favour the flow of K+ into the cell. This influx of
potassium, however, is larger when the membrane potential is more negative than the equilibrium
potential for K+ (~-90mV). As the membrane potential becomes more positive (i.e. during cell
stimulation from a neighbouring cell), the flow of potassium into the cell via the Kir decreases.
Therefore, Kir is responsible for maintaining the resting membrane potential and initiating the
depolarization phase. However, as the membrane potential continues to become more positive, the
channel begins to allow the passage of K+ out of the cell. This outward flow of potassium ions at the
more positive membrane potentials means that the Kir can also aid the final stages of
repolarisation.[33][34]
The voltage-gated potassium channels (Kv) are activated by depolarization. One of the currents
produced by these channels include Ito1 (to= transient outward). These currents have two
components, both of which activate very fast, however one inactivates faster than the other (Ito,fast and
Ito,slow). These channels contribute to the early repolarization phase (phase 1) of the action potential.
Kv also includes a group of channels called the delayed rectifier potassium channels. There are three
main currents produced by these channels, which are named based on the speed at which they
activate: IKs, IKr and IKur (s=slow, r= rapid and ur= ultra-rapid). These currents are responsible for the
plateau phase.[35]

Calcium channels[edit]
There are two voltage-gated calcium channels within cardiac muscle: L-type calcium channels ('L' for
Long-lasting) and T-type calcium channels ('T' for Transient, i.e. short). L-type channels are more
common and are most densely populated within the t-tubule membrane of ventricular cells, whereas
the T-type channels are found mainly within atrial and pacemaker cells, but still to a lesser degree
than L-type channels.
These channels respond to voltage changes across the membrane differently: L-type channels are
activated by more positive membrane potentials, take longer to open and remain open longer than
T-type channels. This means that the T-type channels contribute more to depolarization (phase 0)
whereas L-type channels contribute to the plateau (phase 2).[36]

Autorhythmicity[edit]

Figure 4: The electrical conduction system of the heart

Electrical activity that originates from the sinoatrial node is propagated via the His-Purkinje network,
the fastest conduction pathway within the heart. The electrical signal travels from the sinoatrial node
(SAN), which stimulates the atria to contract, to the atrioventricular node (AVN)which slows down
conduction of the action potential, from the atria to the ventricles. This delay allows the ventricles to
fully fill with blood before contraction. The signal then passes down through a bundle of fibres called
the bundle of His, located between the ventricles, and then to the purkinje fibers at the bottom (apex)
of the heart, causing ventricular contraction. This is known as the electrical conduction system of the
heart, see figure 4.
Other than the SAN, the AVN and purkinje fibres also have pacemaker activity and can therefore
spontaneously generate an action potential. However, these cells usually do not depolarize
spontaneously, simply because, action potential production in the SAN is faster. This means that
before the AVN or purkinje fibres reach the threshold potential for an action potential, they are
depolarized by the oncoming impulse from the SAN[37] This is called "overdrive
suppression".[38] Pacemaker activity of these cells is vital, as it means that if the SAN were to fail,
then the heart could continue to beat, albeit at a lower rate (AVN= 40-60 beats per minute, purkinje
fibres = 20-40 beats per minute). These pacemakers will keep a patient alive until the emergency
team arrives.
An example of premature ventricular contraction, is the classic athletic heart syndrome. Sustained
training of athletes causes a cardiac adaptation where the resting SAN rate is lower (sometimes
around 40 beats per minute). This can lead to atrioventricular block, where the signal from the SAN
is impaired in its path to the ventricles. This leads to uncoordinated contractions between the atria
and ventricles, without the correct delay in between and in severe cases can result in sudden
death.[39]

Regulation by the autonomic nervous system[edit]

The speed of action potential production in pacemaker cells is affected, but not controlled by
the autonomic nervous system.
The sympathetic nervous system (nerves dominant during the bodies fight or flight response)
increase heart rate (positive chronotropy), by decreasing the time to produce an action potential in
the SAN. Nerves from the spinal cord release a molecule called noradrenaline, which binds to and
activates receptors on the pacemaker cell membrane called β1 adrenoceptors. This activates a
protein, called a Gs-protein (s for stimulatory). Activation of this G-protein leads to increased levels
of cAMP in the cell (via the cAMP pathway). cAMP binds to the HCN channels (see above),
increasing the funny current and therefore increasing the rate of depolarization, during the
pacemaker potential. The increased cAMP also increases the opening time of L -type calcium
channels, increasing the Ca2+ current through the channel, speeding up phase 0.[40]
The parasympathetic nervous system (nerves dominant while the body is resting and digesting)
decreases heart rate (negative chronotropy), by increasing the time taken to produce an action
potential in the SAN. A nerve called the vagus nerve, that begins in the brain and travels to the
sinoatrial node, releases a molecule called acetylcholine (ACh) which binds to a receptor located on
the outside of the pacemaker cell, called an M2 muscarinic receptor. This activates a Gi-protein (I for
inhibitory), which is made up of 3 subunits (α, β and γ) which, when activated, separate from the
receptor. The β and γ subunits activate a special set of potassium channels, increasing potassium
flow out of the cell and decreasing membrane potential, meaning that the pacemaker cells take
longer to reach their threshold value.[41] The Gi-protein also inhibits the cAMP pathway therefore
reducing the sympathetic effects caused by the spinal nerves.[42]

See also[edit]
 Electrical conduction system of the heart
 Excitation–contraction coupling
 Action potential
 Antiarrhythmic agents
 Cardiac arrhythmia
 Cardiac pacemaker
 Resting membrane potential
 Ventricular action potential

References[edit]
1. Jump up^ Rudy, Y. (2008) ‘Molecular basis of cardiac action potential repolarization’, Annals of the
New York Academy of Sciences., 1123, pp. 113–8.
2. Jump up^ Kurtenbach, S. and Zoidl, G. (2014b) ‘Gap junction modulation and its implications for
heart function’, 5
3. Jump up^ Soltysinska, E., Speerschneider, T., Winther, S. V. and Thomsen, M. B. (2014) ‘Sinoatrial
node dysfunction induces cardiac arrhythmias in diabetic mice’, 13.
4. Jump up^ Becker, D.E. (2006) ‘Fundamentals of Electrocardiography interpretation’, 53(2).
5. Jump up^ Lote, C. (2012). Principles of Renal Physiology (5th ed.). p. 150. ISBN 9781461437840.
6. ^ Jump up to:a b Santana, Luis F.; Cheng, Edward P.; Lederer, W. Jonathan (2010-12-01). "How does
the shape of the cardiac action potential control calcium signaling and contraction in the
heart?". Journal of Molecular and Cellular Cardiology. 49 (6): 901–
903. doi:10.1016/j.yjmcc.2010.09.005. PMC 3623268  . PMID 20850450.
7. Jump up^ Koivumäki, Jussi T.; Korhonen, Topi; Tavi, Pasi (2011-01-01). "Impact of Sarcoplasmic
Reticulum Calcium Release on Calcium Dynamics and Action Potential Morphology in Human Atrial
Myocytes: A Computational Study". PLoS Computational Biology. 7 (1):
e1001067. doi:10.1371/journal.pcbi.1001067. PMC 3029229  . PMID 21298076.
8. ^ Jump up to:a b c d Santana, L.F., Cheng, E.P. and Lederer, J.W. (2010a) ‘How does the shape of the
cardiac action potential control calcium signaling and contraction in the heart?’, 49(6).
9. Jump up^ Morad M., Tung L. (1982). "Ionic events responsible for the cardiac resting and action
potential". The American Journal of Cardiology. 49 (3): 584–594. doi:10.1016/s0002-9149(82)80016-
7.
10. Jump up^ Grunnet M (2010). "Repolarization of the cardiac action potential. Does an increase in
repolarization capacity constitute a new anti-arrhythmic principle?". Acta Physiologica. 198: 1–
48. doi:10.1111/j.1748-1716.2009.02072.x.
11. ^ Jump up to:a b DiFrancesco, Dario (2010-02-19). "The role of the funny current in pacemaker
activity". Circulation Research. 106 (3): 434–
446. doi:10.1161/CIRCRESAHA.109.208041. ISSN 1524-4571. PMID 20167941.
12. Jump up^ Joung, B., Chen, P. and Lin, S. (2011) ‘The role of the calcium and the voltage clocks in
sinoatrial node dysfunction’, Yonsei medical journal., 52(2), pp. 211–9
13. Jump up^ Shih, H T (1994-01-01). "Anatomy of the action potential in the heart". Texas Heart
Institute Journal. 21 (1): 30–41. ISSN 0730-2347. PMC 325129  . PMID 7514060.
14. Jump up^ Purves et al. 2008, pp. 26–28.
15. Jump up^ Rhoades & Bell 2009, p. 45.
16. Jump up^ Sherwood 2012, p. 311.
17. Jump up^ Grunnet M (2010b). "Repolarization of the cardiac action potential. Does an increase in
repolarization capacity constitute a new anti-arrhythmic principle?". Acta Physiologica. 198: 1–
48. doi:10.1111/j.1748-1716.2009.02072.x.
18. Jump up^ Kubo, Y; Adelman, JP; Clapham, DE; Jan, LY; et al. (2005). "International Union of
Pharmacology. LIV. Nomenclature and molecular relationships of inwardly rectifying potassium
channels". Pharmacol Rev. 57 (4): 509–26. doi:10.1124/pr.57.4.11. PMID 16382105.
19. Jump up^ Grunnet, M. (2010b) ‘Repolarization of the cardiac action potential. Does an increase in
repolarization capacity constitute a new anti-arrhythmic principle?’, Acta Physiologica, 198, pp. 1–48.
doi: 10.1111/j.1748-1716.2009.02072.x.
20. Jump up^ Clark, R.B., Mangoni, M.E., Lueger, A., Couette, B., Nargeot, J. and Giles, W.R. (2004) ‘A
rapidly activating delayed rectifier K+ current regulates pacemaker activity in adult mouse sinoatrial
node cells’, Article, 286(5), pp. 1757–1766. doi:10.1152/ajpheart.00753.2003
21. Jump up^ Purves et al. 2008, p. 49.
22. Jump up^ Bullock, TH; Orkand, R; Grinnell, A (1977). Introduction to Nervous Systems. New York:
W. H. Freeman. p. 151. ISBN 0716700301.
23. Jump up^ Sherwood 2008, p. 316.
24. Jump up^ Dubin. Ion Adventure in the Heartland Volume 1. Cover Publishing Company.
p. 145. ISBN 0-912912-11-1.
25. Jump up^ Goodenough, Daniel A.; Paul, David L. (2009-07-01). "Gap junctions". Cold Spring Harbor
Perspectives in Biology. 1 (1): a002576. doi:10.1101/cshperspect.a002576. ISSN 1943-
0264. PMC 2742079  . PMID 20066080.
26. Jump up^ Severs, Nicholas J. (2002-12-01). "Gap junction remodeling in heart failure". Journal of
Cardiac Failure. 8 (6 Suppl): S293–299. doi:10.1054/jcaf.2002.129255. ISSN 1071-
9164. PMID 12555135.
27. Jump up^ Sherwood 2008, pp. 248-50.
28. Jump up^ "SCN5A sodium channel, voltage-gated, type V, alpha subunit [Homo sapiens (human)]".
National Center for Biotechnology Information.
29. Jump up^ Lacerda, AE; Kim, HS; Ruth, P; Perez-Reyes, E; et al. (August 1991). "Normalization of
current kinetics by interaction between the alpha 1 and beta subunits of the skeletal muscle
dihydropyridine-sensitive Ca2+ channel". Nature. 352 (6335): 527–
30. doi:10.1038/352527a0. PMID 1650913.
30. Jump up^ Purves, Dale; Augustine, George J.; Fitzpatrick, David; Katz, Lawrence C.; LaMantia,
Anthony-Samuel; McNamara, James O.; Williams, S. Mark (2001-01-01). "The Molecular Structure of
Ion Channels".
31. Jump up^ Sheng, Morgan. "Ion channels and receptors" (PDF). Retrieved 2013-03-14.
32. Jump up^ Sherwood 2012, pp. 310-1.
33. Jump up^ Hibino, Hiroshi; Inanobe, Atsushi; Furutani, Kazuharu; Murakami, Shingo; Findlay, Ian;
Kurachi, Yoshihisa (2010-01-01). "Inwardly rectifying potassium channels: their structure, function,
and physiological roles". Physiological Reviews. 90 (1): 291–
366. doi:10.1152/physrev.00021.2009. ISSN 1522-1210. PMID 20086079.
 34. Jump up^ Dhamoon, Amit S.; Jalife, José (2005-03-01). "The inward rectifier current (IK1) controls
cardiac excitability and is involved in arrhythmogenesis". Heart Rhythm. 2 (3): 316–
324. doi:10.1016/j.hrthm.2004.11.012. ISSN 1547-5271. PMID 15851327.
35. Jump up^ Snyders, D. J. (1999-05-01). "Structure and function of cardiac potassium
channels". Cardiovascular Research. 42 (2): 377–390. doi:10.1016/s0008-6363(99)00071-
1. ISSN 0008-6363. PMID 10533574.
36. Jump up^ Nargeot, J. (2000-03-31). "A tale of two (Calcium) channels". Circulation Research. 86 (6):
613–615. doi:10.1161/01.res.86.6.613. ISSN 0009-7330. PMID 10746994.
37. Jump up^ Tsien, R. W.; Carpenter, D. O. (1978-06-01). "Ionic mechanisms of pacemaker activity in
cardiac Purkinje fibers". Federation Proceedings. 37 (8): 2127–2131. ISSN 0014-9446. PMID 350631.
38. Jump up^ Vassalle, M. (1977). "The relationship among cardiac pacemakers: Overdrive
suppression". Circulation Research. 41 (3): 269–77. doi:10.1161/01.res.41.3.269. PMID 330018.
39. Jump up^ Fagard R (2003-12-01). "Athlete's heart". Heart. 89 (12): 1455–
61. doi:10.1136/heart.89.12.1455. PMC 1767992  . PMID 14617564.
40. Jump up^ DiFrancesco, D.; Tortora, P. (1991-05-09). "Direct activation of cardiac pacemaker
channels by intracellular cyclic AMP". Nature. 351 (6322): 145–
147. doi:10.1038/351145a0. ISSN 0028-0836. PMID 1709448.
41. Jump up^ Osterrieder, W.; Noma, A.; Trautwein, W. (1980-07-01). "On the kinetics of the potassium
channel activated by acetylcholine in the S-A node of the rabbit heart". Pflügers Archiv: European
Journal of Physiology. 386 (2): 101–109. doi:10.1007/bf00584196. ISSN 0031-6768. PMID 6253873.
42. Jump up^ Demir, Semahat S.; Clark, John W.; Giles, Wayne R. (1999-06-01). "Parasympathetic
modulation of sinoatrial node pacemaker activity in rabbit heart: a unifying model". American Journal
of Physiology. Heart and Circulatory Physiology. 276 (6): H2221–H2244. ISSN 0363-
6135. PMID 10362707.

Bibliography[edit]
 Rudy, Yoram (March 2008). "Molecular Basis of Cardiac Action Potential Repolarization". Annals of the
New York Academy of Sciences. 1123 (Control and Regulation of Transport Phenomena in the Cardiac
System): 113–8. doi:10.1196/annals.1420.013.
 Sherwood, L. (2008). Human Physiology, From Cells to Systems (7th ed.). Cengage
Learning. ISBN 9780495391845.
 Sherwood, L. (2012). Human Physiology, From Cells to Systems (8th [revised] ed.). Cengage
Learning. ISBN 9781111577438.
 Purves, D; Augustine, GJ; Fitzpatrick, D; Hall, WC; et al. (2008). Neuroscience (4th ed.). Sunderland, MA:
Sinauer Associates. ISBN 9780878936977.
 Rhoades, R.; Bell, D.R., eds. (2009). Medical Physiology: Principles for Clinical Medicine. Lippincott
Williams & Wilkins. ISBN 9780781768528.

External links[edit]
 Interactive animation illustrating the generation of a cardiac action potential
 Interactive mathematical models of cardiac action potential and other generic action potentials

[hide]

Physiology of the cardiovascular system

  Cardiac cycle

 Cardiac output

 Heart rate

 Stroke volume

 Stroke volume

 End-diastolic volume

 End-systolic volume
diac output

 Afterload

 Preload

 Frank–Starling law

 Cardiac function curve

 Venous return curve

 Wiggers diagram

 Pressure volume diagram

Ultrasound Fractional shortening = (End-diastolic dimensio