Cardiac Physiology

Electrical Conduction in the Heart

Anatomy of the cardiac conduction system

Sinoatrial (SA) node:

• A compact region of pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias cells (modified myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology) that serves as the primary pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias of the heart
• Located within the subepicardial tissue at the junction of the right atrium and superior vena cava Superior vena cava The venous trunk which returns blood from the head, neck, upper extremities and chest. Mediastinum and Great Vessels: Anatomy
• Depolarizes regularly:
  • Called the sinus rhythm: HR and rhythm are driven by the regular Regular Insulin firing of the SA node (60–100/min).
  • Depolarization Depolarization Membrane Potential generates an electrical signal.
• Signal originates in the SA node → atrial myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology → atrioventricular (AV) node

The AV node:

• A compact region of pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias cells that receives input from the SA node and propagates it toward the ventricles
• Located near the intersection of the interventricular septum Interventricular Septum Ventricular Septal Defect (VSD) and the septal leaflet of the tricuspid valve Tricuspid valve The valve consisting of three cusps situated between the right atrium and right ventricle of the heart. Heart: Anatomy
• 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 Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias with a slower rhythm (HR: 40–60/min).

Bundle of His Bundle of His Small band of specialized cardiac muscle fibers that originates in the atrioventricular node and extends into the membranous part of the interventricular septum. The bundle of his, consisting of the left and the right bundle branches, conducts the electrical impulses to the heart ventricles in generation of myocardial contraction. Heart: Anatomy and Purkinje fibers Purkinje fibers Modified cardiac muscle fibers composing the terminal portion of the heart conduction system. Heart: Anatomy:

• Conduct electrical signals through the interventricular septum Interventricular Septum Ventricular Septal Defect (VSD) and ventricular walls
• Common AV bundle (of His): pathway within the interventricular septum Interventricular Septum Ventricular Septal Defect (VSD) 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 Interventricular Septum Ventricular Septal Defect (VSD).
  • Both branches run toward the apex.
• Purkinje fibers Purkinje fibers Modified cardiac muscle fibers composing the terminal portion of the heart conduction system. Heart: Anatomy:
  • 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 Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology:

• Cardiac muscle Cardiac muscle The muscle tissue of the heart. It is composed of striated, involuntary muscle cells connected to form the contractile pump to generate blood flow. Muscle Tissue: Histology 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 Gap Junctions Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. The Cell: Cell 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. 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 Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology: approximately 0.5‒1 m/sec
• AV node: approximately 0.05 m/sec (slowest)
• Bundle of His Bundle of His Small band of specialized cardiac muscle fibers that originates in the atrioventricular node and extends into the membranous part of the interventricular septum. The bundle of his, consisting of the left and the right bundle branches, conducts the electrical impulses to the heart ventricles in generation of myocardial contraction. Heart: Anatomy and the left and right bundle branches: approximately 2 m/sec
• Purkinje fibers Purkinje fibers Modified cardiac muscle fibers composing the terminal portion of the heart conduction system. Heart: Anatomy: approximately 4 m/sec (fastest)
• Ventricular myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology: 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 Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure 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 Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure 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 Resting membrane potential Membrane Potential (RMP)

Nonpacemaker cardiac myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology depolarize only when they receive an electrical stimulus. When nonpacemaker cardiac myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology are not stimulated, they exist in a resting state and have an RMP.

• RMP: the electrical potential across the myocyte membrane Myocyte Membrane Ion Channel Myopathy in its resting state
• Created by membrane permeability and the concentration differences of several key ions:
  • K⁺
  • Na⁺
  • Calcium Calcium A basic element found in nearly all tissues. It is a member of the alkaline earth family of metals with the atomic symbol ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes. Electrolytes ( Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺)
  • Cl^–
• Can be calculated using the complex Goldman-Hodgkin-Katz equation
• Na⁺/K⁺ ATPase pump Pump ACES and RUSH: Resuscitation Ultrasound Protocols:
  • 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 Channels The Cell: Cell Membrane: open at RMP, allowing for a slow trickle of K⁺ out of the cell
• At rest, myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology 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 Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential:
  • An electrical stimulus leads to the opening of voltage-gated ion channels Channels The Cell: Cell Membrane, allowing ions to flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure 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 Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential
  • An action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane 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 Depolarization Membrane Potential):
  • Induced by the voltage change from the action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential generated by pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias cells
  • Voltage-gated Na⁺ channels Channels The Cell: Cell Membrane are activated:
    • Cause a rapid influx of Na⁺
    • The cell becomes less negative.
• Phases 1–3 ( repolarization Repolarization Membrane Potential):
  • Phase 1 Phase 1 Skin: Structure and Functions (initial repolarization Repolarization Membrane Potential):
    • Fast voltage-gated K⁺ channels Channels The Cell: Cell Membrane activated → initial efflux of K⁺
    • Cell becomes more negative.
  • Phase 2 Phase 2 Skin: Structure and Functions (plateau):
    • Long-lasting (L-type) Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane open → influx of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺
    • 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 has minimal overall change: plateau
  • Phase 3 Phase 3 Skin: Structure and Functions ( repolarization Repolarization Membrane Potential to baseline):
    • Delayed K⁺ channels Channels The Cell: Cell Membrane → higher and slower efflux of K⁺
    • The cell becomes more negative, returning to the baseline of ‒90 mV.

Propagation of depolarization Depolarization Membrane Potential

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

• Myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology are connected to each other via gap junctions Gap Junctions Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. The Cell: Cell Junctions.
• Gap junctions Gap Junctions Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. The Cell: Cell Junctions:
  • Membrane-bound protein channels Channels The Cell: Cell Membrane
  • Channels Channels The Cell: Cell Membrane open → ion signals can quickly pass through
• Action potentials (i.e., the flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure of ions) pass through gap junctions Gap Junctions Connections between cells which allow passage of small molecules and electric current. Gap junctions were first described anatomically as regions of close apposition between cells with a narrow (1-2 nm) gap between cell membranes. The variety in the properties of gap junctions is reflected in the number of connexins, the family of proteins which form the junctions. The Cell: Cell Junctions: propagation of action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential to the next myocyte
• Myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology have an absolute refractory period Absolute refractory period Membrane Potential of approximately 250 msec (compared with 1‒2 msec of skeletal muscle).

Electrophysiology of Pacemaker Cells

Action potentials

Pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias cells located in the SA and AV nodes undergo continuous changes in action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential; thus, they do not have a true resting potential.

• Phase 4 ( pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias potential):
  • Slow spontaneous depolarization Depolarization Membrane Potential during diastole Diastole Post-systolic relaxation of the heart, especially the heart ventricles. Cardiac Cycle (relaxation of the heart muscle) from approximately ‒60 mV up to its threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction potential of ‒40 mV
  • Mediated primarily by the “funny” current (I_f) through hyperpolarization-activated cyclic nucleotide-gated (HCN) channels Channels The Cell: Cell Membrane:
    • An inward current of Na⁺
    • An outward current of K⁺
  • Mediated partly by:
    • An inward current of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ through transient or T-type (transient) Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane
    • An outward current of K⁺ through delayed K⁺ channels Channels The Cell: Cell Membrane
• Phase 0 ( depolarization Depolarization Membrane Potential):
  • Occurs when the threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction potential (‒40 mV) is reached
  • Causes voltage-gated L-type Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane to open:
    • Influx of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺
    • The cell becomes more positive.
  • Depolarization Depolarization Membrane Potential is relatively slow because L-type Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane are slower than voltage-gated Na⁺ channels Channels The Cell: Cell Membrane, which trigger Trigger The type of signal that initiates the inspiratory phase by the ventilator Invasive Mechanical Ventilation depolarization Depolarization Membrane Potential in nonpacemaker cells.
• Phase 3 Phase 3 Skin: Structure and Functions ( repolarization Repolarization Membrane Potential):
  • Voltage-gated L-type Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane are inactivated → Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ influx stops
  • Delayed voltage-gated K⁺ channels Channels The Cell: Cell Membrane 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 Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias and nonpacemaker action potentials

Compared with nonpacemaker action potentials, pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias action potentials have the following characteristics:

• Begin at higher voltages
• No resting potential
• Slower depolarization Depolarization Membrane Potential
• Faster repolarization Repolarization Membrane Potential

Regulation of the HR

Heart rate, chronotropy, and dromotropy

Chronotropy refers to the modulation of HR at the level of the pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias cells. The SA node rate is primarily controlled by the ANS ANS The ans is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ans consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System: Anatomy (sympathetic and parasympathetic nerves).

• Normal resting HR: 60–100/min
• Tachycardia Tachycardia Abnormally rapid heartbeat, usually with a heart rate above 100 beats per minute for adults. Tachycardia accompanied by disturbance in the cardiac depolarization (cardiac arrhythmia) is called tachyarrhythmia. Sepsis in Children: HR > 100/min
• Bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias: HR < 60/min
• Negative chronotropy:
  • Slowing down of the HR
  • Mediated by parasympathetic/vagal activation:
    • By acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS
    • At the muscarinic (M₂) receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors
• Positive chronotropy:
  • Increase in the HR
  • Mediated by sympathetic activation:
    • By norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS
    • At the β₁-adrenergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. 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 ANS The ans is a component of the peripheral nervous system that uses both afferent (sensory) and efferent (effector) neurons, which control the functioning of the internal organs and involuntary processes via connections with the CNS. The ans consists of the sympathetic and parasympathetic nervous systems. Autonomic Nervous System: Anatomy):

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

Parasympathetic control of HR

Cholinergic nerves release acetylcholine Acetylcholine A neurotransmitter found at neuromuscular junctions, autonomic ganglia, parasympathetic effector junctions, a subset of sympathetic effector junctions, and at many sites in the central nervous system. Receptors and Neurotransmitters of the CNS, which brings about 2 primary changes within myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology:

• Decreases cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors levels, which in turn:
  • Slows down depolarization by ↓ the “funny” current:
    • → ↓ Na⁺ flow Flow Blood flows through the heart, arteries, capillaries, and veins in a closed, continuous circuit. Flow is the movement of volume per unit of time. Flow is affected by the pressure gradient and the resistance fluid encounters between 2 points. Vascular resistance is the opposition to flow, which is caused primarily by blood friction against vessel walls. Vascular Resistance, Flow, and Mean Arterial Pressure 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 Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction (phase 4 line is flatter)
  • ↓ Phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing of the Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channel → ↓ Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ influx → moving the threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction 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 Channels The Cell: Cell Membrane → ↑ K⁺ efflux:
  • Makes the cell more negative
  • → Longer time to reach the threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction potential

Sympathetic control of HR

Norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS is released from sympathetic nerves, which binds to β₁-adrenergic receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors in the myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology and causes an intracellular increase in cAMP cAMP An adenine nucleotide containing one phosphate group which is esterified to both the 3′- and 5′-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and acth. Phosphodiesterase Inhibitors, thereby increasing the HR via 2 mechanisms:

• ↑ “Funny” current through the HCN receptors Receptors Receptors are proteins located either on the surface of or within a cell that can bind to signaling molecules known as ligands (e.g., hormones) and cause some type of response within the cell. Receptors → ↑ Na⁺ influx during phase 4 → increases the rate of depolarization Depolarization Membrane Potential (steeper slope of phase 4)
• ↑ Phosphorylation Phosphorylation The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety. Post-translational Protein Processing of Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane → ↑ Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ influx → lowering of action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential threshold Threshold Minimum voltage necessary to generate an action potential (an all-or-none response) Skeletal Muscle Contraction (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 Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias activity

• ↑ Thyroid Thyroid The thyroid gland is one of the largest endocrine glands in the human body. The thyroid gland is a highly vascular, brownish-red gland located in the visceral compartment of the anterior region of the neck. Thyroid Gland: Anatomy hormones Hormones Hormones are messenger molecules that are synthesized in one part of the body and move through the bloodstream to exert specific regulatory effects on another part of the body. Hormones play critical roles in coordinating cellular activities throughout the body in response to the constant changes in both the internal and external environments. Hormones: Overview and Types (i.e., T3 T3 A T3 thyroid hormone normally synthesized and secreted by the thyroid gland in much smaller quantities than thyroxine (T4). Most T3 is derived from peripheral monodeiodination of T4 at the 5′ position of the outer ring of the iodothyronine nucleus. The hormone finally delivered and used by the tissues is mainly t3. Thyroid Hormones and T4 T4 The major hormone derived from the thyroid gland. Thyroxine is synthesized via the iodination of tyrosines (monoiodotyrosine) and the coupling of iodotyrosines (diiodotyrosine) in the thyroglobulin. Thyroxine is released from thyroglobulin by proteolysis and secreted into the blood. Thyroxine is peripherally deiodinated to form triiodothyronine which exerts a broad spectrum of stimulatory effects on cell metabolism. Thyroid Hormones) → ↑ HR
• ↑ Circulating catecholamines Catecholamines A general class of ortho-dihydroxyphenylalkylamines derived from tyrosine. Adrenal Hormones (e.g., epinephrine Epinephrine The active sympathomimetic hormone from the adrenal medulla. It stimulates both the alpha- and beta- adrenergic systems, causes systemic vasoconstriction and gastrointestinal relaxation, stimulates the heart, and dilates bronchi and cerebral vessels. Sympathomimetic Drugs and norepinephrine Norepinephrine Precursor of epinephrine that is secreted by the adrenal medulla and is a widespread central and autonomic neurotransmitter. Norepinephrine is the principal transmitter of most postganglionic sympathetic fibers, and of the diffuse projection system in the brain that arises from the locus ceruleus. Receptors and Neurotransmitters of the CNS from the adrenal medulla Adrenal Medulla The inner portion of the adrenal gland. Derived from ectoderm, adrenal medulla consists mainly of chromaffin cells that produces and stores a number of neurotransmitters, mainly adrenaline (epinephrine) and norepinephrine. The activity of the adrenal medulla is regulated by the sympathetic nervous system. Adrenal Glands: Anatomy) → ↑ 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 Ischemia A hypoperfusion of the blood through an organ or tissue caused by a pathologic constriction or obstruction of its blood vessels, or an absence of blood circulation. Ischemic Cell Damage (↓ in O₂) → ↓ HR (works through a different K⁺ channel)
• Drugs:
  • Antiarrhythmic agents
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  • β-adrenergic blockers
  • Digoxin Digoxin A cardiotonic glycoside obtained mainly from digitalis lanata; it consists of three sugars and the aglycone digoxigenin. Digoxin has positive inotropic and negative chronotropic activity. It is used to control ventricular rate in atrial fibrillation and in the management of congestive heart failure with atrial fibrillation. Its use in congestive heart failure and sinus rhythm is less certain. The margin between toxic and therapeutic doses is small. Cardiac Glycosides

Clinical Relevance

Atrioventricular node Atrioventricular node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. Heart: Anatomy blocks

Atrioventricular node Atrioventricular node A small nodular mass of specialized muscle fibers located in the interatrial septum near the opening of the coronary sinus. It gives rise to the atrioventricular bundle of the conduction system of the heart. Heart: Anatomy 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 Pain An unpleasant sensation induced by noxious stimuli which are detected by nerve endings of nociceptive neurons. Pain: Types and Pathways, 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 Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias 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. 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 (AV 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 (AV block): delayed conduction through the AV node. Some atrial action potentials fail to make it through the AV node, resulting in ventricular bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias.
  • Mobitz type I ( Wenckebach Wenckebach Atrioventricular block (AV block)): 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 Regular Insulin 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 (AV block): a complete block through the AV node resulting in atrial-ventricular dissociation Dissociation Defense Mechanisms (activation and contraction are independent of each other as no atrial impulses reach the ventricles). Affected individuals have ventricular bradycardia Bradycardia Bradyarrhythmia is a rhythm in which the heart rate is less than 60/min. Bradyarrhythmia can be physiologic, without symptoms or hemodynamic change. Pathologic bradyarrhythmia results in reduced cardiac output and hemodynamic instability causing syncope, dizziness, or dyspnea. Bradyarrhythmias driven by an escape Escape With constant immune mechanisms holding unstable tumor cells in equilibrium, tumor-cell variants may emerge. These cancer cells may express fewer antigens on their surfaces or lose their MHC class I expression.Variants may also protect themselves from T-cell attack via expression of IC molecules on their surfaces, like normal cells.Creation of an immunosuppressive state in the microenvironment is another way to grow without immunologic interference. Cancer Immunotherapy pacemaker Pacemaker A device designed to stimulate, by electric impulses, contraction of the heart muscles. It may be temporary (external) or permanent (internal or internal-external). Bradyarrhythmias 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 Myocardial ischemia A disorder of cardiac function caused by insufficient blood flow to the muscle tissue of the heart. The decreased blood flow may be due to narrowing of the coronary arteries (coronary artery disease), to obstruction by a thrombus (coronary thrombosis), or less commonly, to diffuse narrowing of arterioles and other small vessels within the heart. Coronary Heart Disease, 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). Cardiomyopathy: Overview and Types). 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 Interventricular Septum Ventricular Septal Defect (VSD). The block forces electrical signals down the other bundle branch such that the ventricle depolarizes 1st. Electrical waves then travel through the myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology directly to cause depolarization Depolarization Membrane Potential on the affected side.
• 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: a block in 1 of the more distal Purkinje fibers Purkinje fibers Modified cardiac muscle fibers composing the terminal portion of the heart conduction system. Heart: Anatomy. The affected area will receive electrical signals more slowly from the surrounding myocytes Myocytes Mature contractile cells, commonly known as myocytes, that form one of three kinds of muscle. The three types of muscle cells are skeletal, cardiac, and smooth. They are derived from embryonic (precursor) muscle cells called myoblasts. Muscle Tissue: Histology.

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 Channels The Cell: Cell Membrane responsible for the depolarization Depolarization Membrane Potential of cardiomyocytes during phase 0 of the nonpacemaker action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential.
• Class II antiarrhythmics are a group of medications that inhibit the β-adrenergic channels Channels The Cell: Cell Membrane in cardiac muscle Cardiac muscle The muscle tissue of the heart. It is composed of striated, involuntary muscle cells connected to form the contractile pump to generate blood flow. Muscle Tissue: Histology. Drugs in this class are commonly known as beta-blockers Beta-blockers Drugs that bind to but do not activate beta-adrenergic receptors thereby blocking the actions of beta-adrenergic agonists. Adrenergic beta-antagonists are used for treatment of hypertension, cardiac arrhythmias, angina pectoris, glaucoma, migraine headaches, and anxiety. Class 2 Antiarrhythmic Drugs (Beta Blockers).
• Class III antiarrhythmics are a group of medications that inhibit the K⁺ channels Channels The Cell: Cell Membrane responsible for the repolarization Repolarization Membrane Potential of cardiomyocytes during phase 3 Phase 3 Skin: Structure and Functions of the nonpacemaker action potential Action Potential Abrupt changes in the membrane potential that sweep along the cell membrane of excitable cells in response to excitation stimuli. Membrane Potential.
• Class IV antiarrhythmics are a group of medications that inhibit the Ca CA Condylomata acuminata are a clinical manifestation of genital HPV infection. Condylomata acuminata are described as raised, pearly, flesh-colored, papular, cauliflower-like lesions seen in the anogenital region that may cause itching, pain, or bleeding. Condylomata Acuminata (Genital Warts)²⁺ channels Channels The Cell: Cell Membrane that are active during the repolarization Repolarization Membrane Potential of cardiomyocytes.