Electrical Conduction in the Heart

Anatomy of the cardiac conduction system

Sinoatrial (SA) node:

• A compact region of pacemaker cells (modified myocytes) that serves as the primary pacemaker of the heart
• Located within the subepicardial tissue at the junction of the right atrium and superior vena cava
• Depolarizes regularly:
  • Called the sinus rhythm: HR and rhythm are driven by the regular firing of the SA node (60–100/min).
  • Depolarization generates an electrical signal.
• Signal originates in the SA node → atrial myocytes → atrioventricular (AV) node

The AV node:

• A compact region of pacemaker cells that receives input from the SA node and propagates it toward the ventricles
• Located near the intersection of the interventricular septum and the septal leaflet of the tricuspid valve
• Characterized by slow conduction and a long refractory period:
  • Causes a delay in propagation of electrical signal to the ventricles
  • Allows ventricles to fill with blood from the atrial contraction before the ventricles contract
• If the SA node fails, the AV node has its own autorhythmicity and can serve as the primary pacemaker with a slower rhythm (HR: 40–60/min).

Bundle of His and Purkinje fibers:

• Conduct electrical signals through the interventricular septum and ventricular walls
• Common AV bundle (of His): pathway within the interventricular septum by which the signal leaves the AV node
• Right and left bundle branches:
  • AV bundle divides into right and left bundles within the interventricular septum.
  • Both branches run toward the apex.
• Purkinje fibers:
  • Arise from the bundle branches
  • Spread throughout the ventricular walls
  • Fastest conduction fibers
  • Have their own intrinsic rhythm of 30–40/min (although this is not fast enough to sustain life)

Nonpacemaker myocytes:

• Cardiac muscle cells that are not part of the SA or AV nodes
• Contract when they receive an electrical signal
• Connected to each other via gap junctions → capable of conducting electrical signals from 1 cell to the next

Summary of the electrical pathway

• Clinically, the electrophysiological activity of the heart can be monitored using ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG). 
• The diagram below summarizes the formation and propagation of the electrical wave.

Conduction times

Action potentials travel at different speeds through different tissues and segments of the conduction system.

• Atrial myocytes: approximately 0.5‒1 m/sec
• AV node: approximately 0.05 m/sec (slowest)
• Bundle of His and the left and right bundle branches: approximately 2 m/sec
• Purkinje fibers: approximately 4 m/sec (fastest)
• Ventricular myocytes: approximately 0.5 m/sec

Electrophysiology of Nonpacemaker Myocytes

Background

• Electrical potential:
  • Difference in the concentration of charged particles between 1 point and another (in physiology, usually across a cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane)
  • A form of potential energy
  • Capable of producing an electrical current
  • Unit: volts
• Electrical current:
  • The flow of charged particles from 1 point to another (in physiology, usually across a cell membrane Cell Membrane A cell membrane (also known as the plasma membrane or plasmalemma) is a biological membrane that separates the cell contents from the outside environment. A cell membrane is composed of a phospholipid bilayer and proteins that function to protect cellular DNA and mediate the exchange of ions and molecules. The Cell: Cell Membrane)
  • Written as “I” (e.g., flow of K⁺ ions: I_K+)
• Polarization:
  • Electrical potential exists across a membrane.
  • In cardiac physiology:
    • Hyperpolarized state: The cell is in a more negative state (i.e., a larger concentration gradient is present).
    • Depolarized state: The cell is in a less negative/slightly positive state (i.e., a smaller concentration gradient is present).

Resting membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential (RMP)

Nonpacemaker cardiac myocytes depolarize only when they receive an electrical stimulus. When nonpacemaker cardiac myocytes are not stimulated, they exist in a resting state and have an RMP.

• RMP: the electrical potential across the myocyte membrane in its resting state
• Created by membrane permeability and the concentration differences of several key ions:
  • K⁺
  • Na⁺
  • Calcium (Ca²⁺)
  • Cl^–
• Can be calculated using the complex Goldman-Hodgkin-Katz equation
• Na⁺/K⁺ ATPase pump:
  • Establishes the major concentration differentials of K⁺ and Na⁺ across the membrane
  • Pumps 3 Na⁺ out of the cell in exchange for bringing 2 K⁺ into the cell
  • → 3 positive charges move out and only 2 positive charges move in
  • → inside of the cell becomes more negative
• Voltage-gated K⁺ channels: open at RMP, allowing for a slow trickle of K⁺ out of the cell
• At rest, myocytes are in a hyperpolarized state:
  • RMP = –90 mV
  • Depicted by an isoelectric (flat) line on graphs showing how the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential changes over time

Action potentials

• Action potential:
  • An electrical stimulus leads to the opening of voltage-gated ion channels, allowing ions to flow into and out of the cell down their concentration gradients (i.e., ion currents).
  • While the current is flowing, the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential actively changes → action potential
  • An action potential can be divided into phases 0‒4 (usually described as beginning with 4).
  • Often depicted as a graph, showing the change in membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential over time
• Phase 4 (resting potential):
  • RMP = ‒90 mV
  • Depicted by an isoelectric line
• Phase 0 (rapid depolarization):
  • Induced by the voltage change from the action potential generated by pacemaker cells
  • Voltage-gated Na⁺ channels are activated:
    • Cause a rapid influx of Na⁺
    • The cell becomes less negative.
• Phases 1–3 (repolarization):
  • Phase 1 (initial repolarization):
    • Fast voltage-gated K⁺ channels activated → initial efflux of K⁺
    • Cell becomes more negative.
  • Phase 2 (plateau):
    • Long-lasting (L-type) Ca²⁺ channels open → influx of Ca²⁺
    • Membrane potential has minimal overall change: plateau
  • Phase 3 (repolarization to baseline):
    • Delayed K⁺ channels → higher and slower efflux of K⁺
    • The cell becomes more negative, returning to the baseline of ‒90 mV.

Propagation of depolarization

Propagation refers to how electrical signals spread to every myocyte in the heart.

• Myocytes are connected to each other via gap junctions.
• Gap junctions:
  • Membrane-bound protein channels
  • Channels open → ion signals can quickly pass through
• Action potentials (i.e., the flow of ions) pass through gap junctions: propagation of action potential to the next myocyte
• Myocytes have an absolute refractory period of approximately 250 msec (compared with 1‒2 msec of skeletal muscle).

Electrophysiology of Pacemaker Cells

Action potentials

Pacemaker cells located in the SA and AV nodes undergo continuous changes in action potential; thus, they do not have a true resting potential.

• Phase 4 (pacemaker potential):
  • Slow spontaneous depolarization during diastole (relaxation of the heart muscle) from approximately ‒60 mV up to its threshold potential of ‒40 mV
  • Mediated primarily by the “funny” current (I_f) through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels:
    • An inward current of Na⁺
    • An outward current of K⁺
  • Mediated partly by:
    • An inward current of Ca²⁺ through transient or T-type (transient) Ca²⁺ channels
    • An outward current of K⁺ through delayed K⁺ channels
• Phase 0 (depolarization):
  • Occurs when the threshold potential (‒40 mV) is reached
  • Causes voltage-gated L-type Ca²⁺ channels to open:
    • Influx of Ca²⁺
    • The cell becomes more positive.
  • Depolarization is relatively slow because L-type Ca²⁺ channels are slower than voltage-gated Na⁺ channels, which trigger depolarization in nonpacemaker cells.
• Phase 3 (repolarization):
  • Voltage-gated L-type Ca²⁺ channels are inactivated → Ca²⁺ influx stops
  • Delayed voltage-gated K⁺ channels open → efflux of K⁺ → membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential becomes more negative again

Comparison of pacemaker and nonpacemaker action potentials

Compared with nonpacemaker action potentials, pacemaker action potentials have the following characteristics:

• Begin at higher voltages
• No resting potential
• Slower depolarization
• Faster repolarization

Regulation of the HR

Heart rate, chronotropy, and dromotropy

Chronotropy refers to the modulation of HR at the level of the pacemaker cells. The SA node rate is primarily controlled by the ANS (sympathetic and parasympathetic nerves).

• Normal resting HR: 60–100/min
• Tachycardia: HR > 100/min
• Bradycardia: HR < 60/min
• Negative chronotropy:
  • Slowing down of the HR
  • Mediated by parasympathetic/vagal activation:
    • By acetylcholine
    • At the muscarinic (M₂) receptors
• Positive chronotropy:
  • Increase in the HR
  • Mediated by sympathetic activation:
    • By norepinephrine
    • At the β₁-adrenergic receptors
• There is a constant, low level of vagal tone slightly suppressing the intrinsic rate of the SA node.

Dromotropy is the modulation of conduction velocity through the AV node (also controlled by the ANS):

• Sympathetic: speeds up conduction through the AV node
• Parasympathetic: slows down conduction through the AV node

Parasympathetic control of HR

Cholinergic nerves release acetylcholine, which brings about 2 primary changes within myocytes:

• Decreases cAMP levels, which in turn:
  • Slows down depolarization by ↓ the “funny” current:
    • → ↓ Na⁺ flow into the cell during phase 4
    • → Longer time for the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential to reach its threshold (phase 4 line is flatter)
  • ↓ Phosphorylation of the Ca²⁺ channel → ↓ Ca²⁺ influx → moving the threshold potential farther from the current membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential
• Opens more K⁺ channels → ↑ K⁺ efflux:
  • Makes the cell more negative
  • → Longer time to reach the threshold potential

Sympathetic control of HR

Norepinephrine is released from sympathetic nerves, which binds to β₁-adrenergic receptors in the myocytes and causes an intracellular increase in cAMP, thereby increasing the HR via 2 mechanisms:

• ↑ “Funny” current through the HCN receptors → ↑ Na⁺ influx during phase 4 → increases the rate of depolarization (steeper slope of phase 4)
• ↑ Phosphorylation of Ca²⁺ channels → ↑ Ca²⁺ influx → lowering of action potential threshold (moves closer to the membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential)

Other factors influencing pacemaker activity

• ↑ Thyroid hormones Thyroid hormones The 2 primary thyroid hormones are triiodothyronine (T3) and thyroxine (T4). These hormones are synthesized and secreted by the thyroid, and they are responsible for stimulating metabolism in most cells of the body. Their secretion is regulated primarily by thyroid-stimulating hormone (TSH), which is produced by the pituitary gland. Thyroid Hormones (i.e., T3 and T4) → ↑ HR
• ↑ Circulating catecholamines (e.g., epinephrine and norepinephrine from the adrenal medulla) → ↑ HR
• ↑ K⁺ → ↓ HR (because K⁺ affects membrane potential Membrane potential The membrane potential is the difference in electric charge between the interior and the exterior of a cell. All living cells maintain a potential difference across the membrane thanks to the insulating properties of their plasma membranes (PMs) and the selective transport of ions across this membrane by transporters. Membrane Potential)
• Ischemia (↓ in O₂) → ↓ HR (works through a different K⁺ channel)
• Drugs:
  • Antiarrhythmic agents
  • Ca²⁺ channel blockers
  • β-adrenergic blockers
  • Digoxin

Clinical Relevance

Atrioventricular node blocks

Atrioventricular node blocks occur when an anatomical or functional impairment of the conduction system of the heart produces a delay or interruption in the transmission of action potentials from the atria to the ventricles through the AV node. Affected individuals may be asymptomatic or may present with syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope, chest pain Chest Pain Chest pain is one of the most common and challenging complaints that may present in an inpatient and outpatient setting. The differential diagnosis of chest pain is large and includes cardiac, gastrointestinal, pulmonary, musculoskeletal, and psychiatric etiologies. Chest Pain, dyspnea Dyspnea Dyspnea is the subjective sensation of breathing discomfort. Dyspnea is a normal manifestation of heavy physical or psychological exertion, but also may be caused by underlying conditions (both pulmonary and extrapulmonary). Dyspnea, and bradycardia depending on the severity of the block. Diagnosis is established based on ECG ECG An electrocardiogram (ECG) is a graphic representation of the electrical activity of the heart plotted against time. Adhesive electrodes are affixed to the skin surface allowing measurement of cardiac impulses from many angles. The ECG provides 3-dimensional information about the conduction system of the heart, the myocardium, and other cardiac structures. Normal Electrocardiogram (ECG), and treatment is based on the type of block and hemodynamic stability of the affected individual.

• 1st-degree AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block: delayed conduction through the AV node. Affected individuals have sinus rhythm; however, their overall HR is slower.
• 2nd-degree AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block: delayed conduction through the AV node. Some atrial action potentials fail to make it through the AV node, resulting in ventricular bradycardia.
  • Mobitz type I (Wenckebach): progressive increase in conduction delay until a signal fails to make it through the AV node altogether, resulting in the signal (and thus a mechanical contraction) being “dropped.”
  • Mobitz type II: there is no progressive increase in delayed conduction; however, conduction through the AV node is intermittent with some “dropped” signals that do not make it through to the ventricles. Dropped signals often occur in a regular pattern (e.g., 2:1 pattern). Mobitz type II block almost always results from conduction system disease below the level of the AV node.
• 3rd-degree AV block AV block Atrioventricular (AV) block is a bradyarrhythmia caused by delay, or interruption, in the electrical conduction between the atria and the ventricles. Atrioventricular block occurs due to either anatomic or functional impairment, and is classified into 3 types. Atrioventricular Block: a complete block through the AV node resulting in atrial-ventricular dissociation (activation and contraction are independent of each other as no atrial impulses reach the ventricles). Affected individuals have ventricular bradycardia driven by an escape pacemaker distal to the block.

Bundle branch and fascicular blocks Fascicular Blocks Bundle branch and fascicular blocks occur when the normal electrical activity in the His-Purkinje system is interrupted. These blocks can be due to many etiologies that may affect the structure of the heart or the conduction system directly. Bundle Branch and Fascicular Blocks

Bundle branch and fascicular blocks Fascicular Blocks Bundle branch and fascicular blocks occur when the normal electrical activity in the His-Purkinje system is interrupted. These blocks can be due to many etiologies that may affect the structure of the heart or the conduction system directly. Bundle Branch and Fascicular Blocks occur when normal electrical activity in the His-Purkinje system is interrupted. Bundle branch and fascicular blocks Fascicular Blocks Bundle branch and fascicular blocks occur when the normal electrical activity in the His-Purkinje system is interrupted. These blocks can be due to many etiologies that may affect the structure of the heart or the conduction system directly. Bundle Branch and Fascicular Blocks can occur due to many etiologies that may affect the structure of the heart or the conduction system directly (e.g., myocardial ischemia, myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis, cardiomyopathy Cardiomyopathy Cardiomyopathy refers to a group of myocardial diseases associated with structural changes of the heart muscles (myocardium) and impaired systolic and/or diastolic function in the absence of other heart disorders (coronary artery disease, hypertension, valvular disease, and congenital heart disease). Overview of Cardiomyopathies). Although usually asymptomatic, bundle branch and fascicular blocks Fascicular Blocks Bundle branch and fascicular blocks occur when the normal electrical activity in the His-Purkinje system is interrupted. These blocks can be due to many etiologies that may affect the structure of the heart or the conduction system directly. Bundle Branch and Fascicular Blocks may occasionally cause syncope Syncope Syncope is a short-term loss of consciousness and loss of postural stability followed by spontaneous return of consciousness to the previous neurologic baseline without the need for resuscitation. The condition is caused by transient interruption of cerebral blood flow that may be benign or related to a underlying life-threatening condition. Syncope.

• Bundle branch blocks Bundle Branch Blocks Bundle branch and fascicular blocks occur when the normal electrical activity in the His-Purkinje system is interrupted. These blocks can be due to many etiologies that may affect the structure of the heart or the conduction system directly. Bundle Branch and Fascicular Blocks: a block in the downward progression of electrical impulses through 1 of the bundle branches in the interventricular septum. The block forces electrical signals down the other bundle branch such that the ventricle depolarizes 1st. Electrical waves then travel through the myocytes directly to cause depolarization on the affected side.
• Fascicular blocks: a block in 1 of the more distal Purkinje fibers. The affected area will receive electrical signals more slowly from the surrounding myocytes.

Antiarrhythmic medications

The following classes of drugs are used for the treatment of arrhythmias:

• Class I antiarrhythmics are a group of medications that inhibit the Na⁺ channels responsible for the depolarization of cardiomyocytes during phase 0 of the nonpacemaker action potential.
• Class II antiarrhythmics are a group of medications that inhibit the β-adrenergic channels in cardiac muscle. Drugs in this class are commonly known as beta-blockers.
• Class III antiarrhythmics are a group of medications that inhibit the K⁺ channels responsible for the repolarization of cardiomyocytes during phase 3 of the nonpacemaker action potential.
• Class IV antiarrhythmics are a group of medications that inhibit the Ca²⁺ channels that are active during the repolarization of cardiomyocytes.