Electrophysiology of the Heart

Introduction

The heart functions through precisely coordinated electrical events that generate and conduct impulses for effective contraction. Fast-response action potentials activate working myocardium, whereas slow-response action potentials regulate nodal activity. Atrioventricular nodal delay ensures proper timing between atrial and ventricular contraction, allowing optimal ventricular filling.

• The resting membrane potential of ventricular cardiac muscle cells is approximately −90 millivolts, whereas Purkinje fibers have a resting membrane potential of about −90 to −95 millivolts.
• Pacemaker cells possess a less negative maximum diastolic potential, usually around −60 millivolts.
• The sinoatrial node acts as the primary pacemaker because of its intrinsic automaticity.
• Cardiac action potentials are generated when specialized cardiac cells are activated by electrical impulses.
• Electrical activity in the heart depends on the movement of ions across cell membranes.
• These ionic movements occur through specific ion channels and transport mechanisms.
• Different cardiac tissues contain distinct combinations of ionic currents.
• The interaction of sodium, calcium, and potassium currents produces characteristic cardiac action potentials.
• Understanding these ionic currents is essential for interpreting normal cardiac electrophysiology and cardiac rhythm disorders.

Ionic Currents in Cardiac Tissues

• Cardiac electrical activity is produced by four major ionic currents: sodium, calcium, potassium, and pacemaker currents.
• These currents generate and regulate cardiac action potentials.

Table 87.1: Major membrane currents in cardiac tissues.

Ionic Current	Primary Channel	Major Physiological Role
Sodium current (INa)	Voltage-gated sodium channels	Generates rapid depolarization (Phase 0) of fast-response action potentials.
L-type calcium current (ICaL)	L-type calcium channels	Produces the plateau phase of fast-response action potentials and depolarization of nodal cells.
T-type calcium current (ICaT)	T-type calcium channels	Contributes to late pacemaker depolarization in nodal tissue.
Transient outward potassium current (Ito)	Transient outward potassium channels	Participates in early repolarization (Phase 1).
Delayed rectifier potassium current (IKs/IKr)	Delayed rectifier potassium channels	Mediates repolarization (Phase 3) and helps terminate action potentials.
Inward rectifier potassium current (IK1)	Inward rectifier potassium channels	Maintains the resting membrane potential in working myocardial cells.
Pacemaker current (If)	Mixed sodium–potassium channels	Generates spontaneous pacemaker depolarization.
ATP-sensitive and G protein–activated potassium currents	Specialized potassium channels	Modulate membrane excitability and cardiac electrical activity.

Note: Fast-response action potentials occur in atrial muscle, ventricular muscle, and Purkinje fibers, whereas slow-response action potentials occur in the sinoatrial and atrioventricular nodes.

Na+ Current (INa)

• The sodium current (INa) is the major depolarizing current in atrial muscle cells, ventricular muscle cells, and Purkinje fibers.
• It is generated through voltage-gated sodium channels present in the cell membrane.
• Fast sodium channels are abundant in working myocardial cells and Purkinje fibers.
• In contrast, sinoatrial and atrioventricular nodal cells lack significant fast sodium channel activity.
• Consequently, nodal tissues generate slow-response action potentials rather than fast-response action potentials.

Activation of Na+ Channels

• At the resting membrane potential, most voltage-gated sodium channels remain closed but are capable of activation.
• Depolarization produced by a propagated impulse rapidly opens these channels.
• Channel activation occurs within a fraction of a millisecond.
• Opening of sodium channels causes a large inward movement of sodium ions.
• This rapid sodium influx generates the steep upstroke of Phase 0 of the fast-response action potential.
• Cardiac sodium channels possess activation and inactivation gates that regulate ion flow.
• During depolarization, the activation gate opens, allowing sodium entry into the cell.
• Shortly afterward, the inactivation gate closes and terminates sodium influx.

Inactivation of Na+ Channels

• Sodium channel inactivation occurs rapidly after channel opening, usually within approximately 1 millisecond.
• Inactivation prevents continued sodium entry despite ongoing depolarization.
• This process contributes to the termination of the inward sodium current.
• It also assists the transition from depolarization to early repolarization of the action potential.

Importance of INa

• The sodium current is responsible for the rapid depolarization phase of fast-response cardiac action potentials.
• It enables rapid impulse conduction through atrial muscle, ventricular muscle, and Purkinje fibers.
• Activation of sodium channels indirectly influences subsequent calcium and potassium currents that shape the remainder of the action potential.
• Alterations in sodium channel function can significantly affect cardiac excitability and conduction velocity.
• Several antiarrhythmic drugs, including lidocaine, exert their effects by partially blocking cardiac sodium channels and reducing abnormal electrical activity.

Ca++ Currents (ICa)

• The calcium current (ICa) is present in all cardiac tissues and plays a central role in electrical activity and contraction.
• It is mediated by voltage-gated calcium channels located in the cardiac cell membrane.
• Two major types of calcium channels are present in the heart: L-type and T-type calcium channels.
• L-type calcium channels are the predominant channels and contribute most of the calcium current in cardiac tissues.
• T-type calcium channels are less abundant and are involved mainly in pacemaker activity.

L-type Ca2+ Channels (ICaL)

• L-type calcium channels are long-lasting voltage-gated calcium channels.
• They are present in atrial muscle, ventricular muscle, sinoatrial node, atrioventricular node, and the His–Purkinje system.
• These channels contribute to the action potentials of both pacemaker and non-pacemaker cardiac cells.

In Pacemakers

• In the sinoatrial and atrioventricular nodes, opening of L-type calcium channels permits calcium influx into the cell.
• This inward current generates the depolarization phase of nodal action potentials.
• Because calcium channels activate more slowly than fast sodium channels, the upstroke of nodal action potentials is relatively gradual.
• The slower depolarization contributes to the slower conduction velocity characteristic of nodal tissues.
• This property is particularly important in the atrioventricular node, where delayed conduction facilitates coordinated cardiac function.

In Ventricular and Atrial Muscles

• In atrial muscle, ventricular muscle, and Purkinje fibers, L-type calcium channels help maintain the prolonged plateau phase of the action potential.
• Calcium entering through these channels triggers additional calcium release from the sarcoplasmic reticulum by calcium-induced calcium release.
• The resulting increase in intracellular calcium initiates myocardial contraction and regulates contractile force.

T-type Ca2+ Channel (ICaT)

• T-type calcium channels are transient voltage-gated calcium channels present mainly in the sinoatrial and atrioventricular nodes.
• They contribute to the later phase of the pacemaker potential and help spontaneous depolarization in nodal cells.

Other Ca++ Channels

• Cardiac tissue also contains ligand-gated and stretch-sensitive calcium channels.
• Ligand-gated calcium channels are relatively few in number.
• Stretch-sensitive calcium channels open when myocardial fibers are stretched during increased diastolic filling.
• Calcium influx through these channels enhances myocardial contractility and supports the heart’s response to increased preload.

K+ Currents (Ik)

• Potassium currents (IK) are essential for maintaining resting membrane potential and repolarization of cardiac cells.
• Potassium channels in the heart are broadly classified into voltage-gated and ligand-gated channels.
• Major voltage-gated potassium channels include inward rectifier, transient outward, and delayed rectifier potassium channels.
• Ligand-gated potassium channels include G protein–activated, calcium-activated, sodium-activated, arachidonic acid–activated, and adenosine triphosphate–sensitive channels.

Inward Rectifying K+ Channels

• Inward rectifier potassium channels (IK1) are important for maintaining the resting membrane potential of atrial and ventricular myocytes.
• These channels stabilize Phase 4 by promoting potassium conductance at negative membrane potentials.
• They help maintain electrical stability and prevent spontaneous depolarization in working myocardial cells.

Outward Transient Rectifying K+ Channels

• Transient outward potassium channels (Ito) generate the early outward potassium current.
• They are present mainly in atrial and ventricular muscle cells.
• These channels activate rapidly during depolarization and inactivate shortly afterward.
• Potassium efflux through these channels contributes to the initial repolarization of the action potential during Phase 1.

Outward Delayed Rectifying K+ Channels

• Delayed rectifier potassium channels (IKr and IKs) are major repolarizing channels in cardiac tissue.
• They are abundant in atrial myocytes, ventricular myocytes, and Purkinje fibers.
• These channels activate more slowly than transient outward channels.
• Potassium efflux through these channels produces Phase 3 repolarization of the cardiac action potential.
• Their activity helps restore the membrane potential after depolarization.
• In sinoatrial and atrioventricular nodal cells, gradual reduction of delayed rectifier potassium current during Phase 4 contributes to pacemaker depolarization.

G Protein-activated K+ Channel

• G protein–activated potassium channels (IKACh) are stimulated primarily by acetylcholine acting on muscarinic receptors.
• Adenosine can also activate these channels in cardiac tissue.
• They are particularly prominent in sinoatrial and atrioventricular nodal cells.
• Activation increases potassium efflux and causes membrane hyperpolarization.
• This slows pacemaker activity and reduces heart rate.

KATP Channels

• Adenosine triphosphate–sensitive potassium channels (KATP) link cellular metabolism to electrical activity.
• These channels participate in regulating membrane excitability and myocardial contractile function, particularly during metabolic stress and reduced energy availability.

Pacemaker Current (If)

• The pacemaker current (If) is present mainly in sinoatrial and atrioventricular nodal cells.
• It is mediated by hyperpolarization-activated cyclic nucleotide-gated (HCN) channels.
• These channels conduct both sodium and potassium ions and generate a net inward depolarizing current.
• HCN channels are activated by membrane hyperpolarization rather than depolarization.
• Their activation is relatively slow, and the resulting current shows minimal inactivation.
• The pacemaker current begins near the end of Phase 3 and contributes to spontaneous diastolic depolarization.
• This gradual depolarization helps pacemaker cells reach threshold and generate action potentials automatically.
• The pacemaker current is an important contributor to the pacemaker potential.
• In nodal cells, decreasing potassium current and activation of T-type calcium channels also participate significantly in Phase 4 depolarization.

Action Potentials in Cardiac Tissues

• Cardiac tissues exhibit two major types of action potentials: fast-response and slow-response action potentials.
• Fast-response action potentials occur in atrial muscle, ventricular muscle, and Purkinje fibers.
• Slow-response action potentials occur mainly in the sinoatrial and atrioventricular nodes.
• The characteristics of action potentials vary among different cardiac tissues according to their physiological functions.

Fast Response Action Potential

• Fast-response action potentials are responsible for rapid impulse conduction and effective activation of working myocardium.
• They are characterized by five phases, designated as Phases 0 to 4.
• Ventricular muscle cells are commonly used to describe these phases.

Phases and Ionic Basis

Phase 0

• Phase 0 is the phase of rapid depolarization and membrane potential overshoot.
• When the membrane reaches threshold, numerous voltage-gated sodium channels open rapidly.
• Sodium ions enter the cell in large amounts, producing a steep rise in membrane potential.
• This inward sodium current generates the characteristic rapid upstroke of the action potential.
• Opening of some sodium channels promotes activation of additional channels, resulting in a regenerative depolarization process.
• The rapid depolarization of Phase 0 is essential for fast conduction of electrical impulses through the myocardium.

Phase 1

• Phase 1 is a brief period of early repolarization that follows the depolarization peak.
• It occurs primarily because voltage-gated sodium channels become inactivated, terminating the inward sodium current.
• Simultaneously, transient outward potassium channels open and allow potassium ions to leave the cell.
• This transient outward potassium current contributes to a short-lived decline in membrane potential.
• The channels responsible for this current activate rapidly during depolarization and then inactivate quickly.
• Phase 1 represents the transition between rapid depolarization and the subsequent plateau phase of the cardiac action potential.

Phase 2

• Phase 2 is the plateau phase of the fast-response cardiac action potential.
• During this phase, the membrane remains depolarized for a prolonged period.
• The plateau results primarily from sustained calcium influx through L-type calcium channels.
• These channels open relatively slowly but remain active for an extended duration.
• Simultaneous outward movement of potassium ions partially counterbalances calcium entry.
• The balance between calcium influx and potassium efflux maintains the plateau.
• The plateau phase is shorter in atrial muscle cells than in ventricular muscle cells.

Phase 3

• Phase 3 represents final repolarization of the cardiac cell membrane.
• It occurs when calcium channels close and calcium influx declines.
• Potassium permeability increases markedly during this phase.
• Potassium efflux through delayed rectifier potassium channels restores membrane negativity.
• This process returns the membrane potential toward its resting level.

Phase 4

• Phase 4 is the resting phase of the action potential.
• The resting membrane potential is maintained primarily by potassium conductance.
• Inward rectifier potassium channels help stabilize the membrane potential.
• Increased potassium permeability keeps the membrane potential near the potassium equilibrium potential.
• This stable resting state prepares the myocardial cell for the next action potential.

Slow Response Action Potential

• Slow-response action potentials occur in sinoatrial nodal cells, atrioventricular nodal cells, atrioventricular junctional tissue, and occasionally in ischemic or injured myocardium.
• They support pacemaker activity and slow impulse conduction.

Phases and Ionic Basis

• The slow-response action potential is characteristic of sinoatrial and atrioventricular nodal cells.
• It consists mainly of three phases: Phase 0, Phase 3, and Phase 4.
• Phases 1 and 2 are absent or poorly developed in nodal tissues.
• Unlike working myocardial cells, nodal cells do not maintain a stable resting membrane potential.
• Instead, they exhibit spontaneous diastolic depolarization during Phase 4.

Phase 0

• Phase 0 represents depolarization of the nodal cell membrane.
• Depolarization occurs primarily through calcium influx via L-type calcium channels.
• Fast sodium channels contribute little or are absent in normal nodal tissue.
• Consequently, the upstroke of the action potential is gradual and less steep than that of fast-response action potentials.
• The slower upstroke contributes to slow impulse conduction through nodal tissue.

Phase 3

• Phase 3 is the repolarization phase.
• It occurs when calcium channels close and potassium channels open.
• Increased potassium efflux restores membrane negativity and completes repolarization.

Phase 4

• Phase 4 is characterized by spontaneous slow depolarization, also known as the pacemaker potential.
• Early Phase 4 results from a progressive decline in potassium conductance.
• Activation of the pacemaker current and opening of T-type calcium channels contribute to later depolarization.
• Local calcium release from the sarcoplasmic reticulum may also facilitate this process.
• Progressive depolarization eventually reaches threshold and initiates the next action potential, enabling automatic rhythmic activity of the heart.

Pacemaker Potential

• The sinoatrial node generates electrical impulses rhythmically and automatically.
• This automaticity results from spontaneous depolarization that occurs after each action potential.
• The gradual diastolic depolarization that brings the membrane to threshold is called the pacemaker potential or prepotential.
• Pacemaker potential enables the heart to initiate impulses without external stimulation.
• Once threshold is reached, a new action potential is generated and the cycle repeats.

Ionic Basis

In the Initial Part

• The initial part of the pacemaker potential develops during the late phase of repolarization.
• Repolarization of nodal cells is produced primarily by potassium efflux through potassium channels.
• Near the end of repolarization, potassium conductance gradually decreases, a process known as potassium current decay.
• Reduced potassium efflux makes the membrane potential less negative.
• At the same time, pacemaker channels mediated by hyperpolarization-activated cyclic nucleotide-gated channels become active.
• These channels generate the pacemaker current, which carries a net inward depolarizing current.
• The combination of declining potassium conductance and increasing pacemaker current initiates slow diastolic depolarization.
• These mechanisms contribute to the early portion of the pacemaker potential and prepare the membrane for the next heartbeat.

In the Later Part

• The later portion of the pacemaker potential is produced mainly by activation of T-type calcium channels.
• Calcium influx through these channels further depolarizes the membrane and brings it to threshold.
• Once threshold is reached, an action potential is initiated.
• The upstroke of the nodal action potential occurs primarily through calcium entry via L-type calcium channels.
• These channels generate the depolarization phase of sinoatrial and atrioventricular nodal cells.

Other Ions

• Local calcium release from the sarcoplasmic reticulum, often called calcium sparks, may also contribute to spontaneous depolarization.
• Pacemaker activity results from the combined effects of reduced potassium efflux, activation of the pacemaker current, and calcium influx.
• Sodium contributes indirectly through the pacemaker current carried by hyperpolarization-activated cyclic nucleotide-gated channels.
• Pacemaker cells do not possess a stable resting membrane potential.
• Instead, their membrane potential continuously drifts toward threshold during diastole.
• This unstable membrane behavior enables automatic impulse generation.
• Although the sinoatrial node is the primary pacemaker, the atrioventricular node and other latent pacemakers can generate impulses if sinoatrial nodal activity fails.
• The rate of impulse formation depends on the slope of the pacemaker potential.
• Sympathetic stimulation increases the slope of diastolic depolarization and accelerates heart rate.
• Parasympathetic stimulation decreases the slope of depolarization and slows heart rate.

Effect of Vagal Stimulation

• Vagal stimulation decreases heart rate by reducing the rate of impulse generation in the sinoatrial node.
• Acetylcholine released from parasympathetic nerve endings acts primarily on M2 muscarinic receptors.
• Vagal activity hyperpolarizes pacemaker cells and reduces the slope of the pacemaker potential.
• As a result, a longer time is required for the membrane potential to reach threshold.
• This slows the frequency of action potential generation and decreases heart rate.
• Acetylcholine activates G protein–activated potassium channels through M2 receptor signaling.
• Opening of these channels increases potassium efflux and produces membrane hyperpolarization.
• Increased potassium conductance opposes spontaneous depolarization during Phase 4.
• Acetylcholine also decreases intracellular cyclic adenosine monophosphate concentration.
• Reduced cyclic adenosine monophosphate activity decreases the opening probability of pacemaker and calcium channels.
• Consequently, calcium influx through T-type and L-type calcium channels is reduced.
• The decrease in calcium entry further flattens the pacemaker potential and delays threshold attainment.
• Reduced intracellular calcium availability can decrease myocardial contractile force.
• However, the effect of vagal stimulation on ventricular contractility is usually minimal.
• This occurs because ventricular myocardium receives relatively sparse parasympathetic innervation.
• Therefore, vagal stimulation primarily exerts a negative chronotropic effect on the heart, with only a limited influence on ventricular force of contraction.

Effect of Sympathetic Stimulation

• Sympathetic stimulation increases both heart rate and myocardial contractility.
• Norepinephrine released from sympathetic nerve endings binds to beta-1 adrenergic receptors on cardiac cells.
• Activation of these receptors increases intracellular cyclic adenosine monophosphate concentration.
• Increased cyclic adenosine monophosphate enhances the opening of pacemaker and calcium channels.
• The slope of the pacemaker potential becomes steeper, allowing threshold to be reached more rapidly.
• Consequently, the frequency of action potential generation increases and heart rate rises.
• Increased calcium influx into ventricular myocytes elevates intracellular calcium concentration.
• This enhances the force of contraction and improves cardiac output.

Initiation and Propagation of Cardiac Electrical Activity

Excitation is Initiated in the SA Node

• The sinoatrial node normally initiates electrical activity in the heart and serves as the primary pacemaker.
• The wave of depolarization spreads through both atria and reaches the atrioventricular node via specialized internodal pathways.
• This orderly conduction ensures coordinated atrial contraction before ventricular activation.
• The atria and ventricles are electrically insulated by the fibrous cardiac skeleton, including the atrioventricular ring.
• Therefore, electrical impulses cannot pass directly from atrial muscle to ventricular muscle.
• Under normal conditions, conduction from the atria to the ventricles occurs only through the atrioventricular node, atrioventricular bundle, and the ventricular conduction system.

Conduction Slows in AV Node

• Electrical excitation spreads through the atria within approximately 60–90 milliseconds.
• Conduction through the atrioventricular node is much slower, with a velocity of about 0.05 meters per second.
• This slow transmission produces an atrioventricular nodal delay of approximately 0.1 second.
• Atrioventricular nodal delay is an essential feature of normal cardiac conduction.
• Atrioventricular nodal cells are small and possess complex branching patterns, which slow impulse propagation.
• Depolarization in these cells depends mainly on slow L-type calcium channels rather than fast sodium channels.
• Consequently, the upstroke of the action potential is gradual.
• The atrioventricular node also contains relatively few gap junctions, resulting in weaker electrical coupling between adjacent cells.
• These structural and electrophysiological characteristics collectively reduce conduction velocity.

Importance of AV Nodal Delay

• Atrioventricular nodal delay allows atrial depolarization and atrial contraction to occur before ventricular activation.
• This timing ensures that the ventricles remain relaxed during atrial systole and can fill adequately with blood.
• Without this delay, atrial and ventricular contractions would overlap, reducing ventricular filling and cardiac efficiency.
• The delay also serves as a protective mechanism during rapid atrial rhythms.
• In conditions such as atrial fibrillation, many atrial impulses are prevented from reaching the ventricles.
• As a result, ventricular rate remains lower than atrial rate, helping preserve diastolic filling and cardiac output.
• Several drugs, including digoxin and beta-adrenergic blockers, can prolong atrioventricular nodal conduction and reduce ventricular rate.
• Increased parasympathetic activity may further slow conduction and, when excessive, can produce varying degrees of atrioventricular block.

Conduction is Rapid in Ventricles

• After passing through the atrioventricular node, the impulse enters the His–Purkinje system, which includes the atrioventricular bundle, bundle branches, and Purkinje fibers.
• Purkinje fibers possess a large diameter and rapid depolarization characteristics.
• Consequently, they exhibit the highest conduction velocity in the heart, approximately 4 meters per second.
• Rapid conduction allows electrical activation to spread through the ventricles within about 0.08–0.10 second.
• Ventricular depolarization begins in the left side of the interventricular septum.
• The excitation wave then spreads across the septum toward the right side.
• Depolarization subsequently travels toward the apex of the heart through the Purkinje network.
• From the apex, excitation spreads through the ventricular walls toward the base of the heart.
• The impulse progresses from the endocardial surface toward the epicardial surface.
• Therefore, endocardial regions are activated before epicardial regions.
• The final areas to depolarize include parts of the posterobasal left ventricle, the pulmonary conus, and the superior portion of the interventricular septum.
• Ventricular repolarization generally occurs in the opposite direction to depolarization.
• Epicardial regions repolarize earlier than endocardial regions.
• Septal and endocardial areas are among the last regions to complete repolarization.
• Conduction velocity within ordinary ventricular muscle is approximately 1 meter per second.
• Complete ventricular activation occurs within about 75 milliseconds under normal conditions.
• Rapid and coordinated impulse transmission ensures near-simultaneous contraction of ventricular myocardium.
• This synchronization is essential for efficient pressure generation and effective ejection of blood into the pulmonary and systemic circulations.