Cardiac electrophysiology

• Cardiac electrophysiology (also referred to as clinical cardiac electrophysiology , or electrophysiology) is the science of the mechanisms, functions, and performance of the electrical activities of specific regions of the heart.
• The normal electrical conduction in the heart allows the impulse that is generated by the sinoatrial node (SA node) of the heart to be propagated to (and stimulate) the myocardium (Cardiac muscle). The myocardium contracts after stimulation. It is the ordered stimulation of the myocardium that allows efficient contraction of the heart, thereby allowing blood to be pumped throughout the body.

• Proper cardiac function heavily depends on the ability of the cardiomyocytes to receive and propagate an electrical impulse allowing the heart to contract.
• These impulses, known as action potentials, originate and travel through the cardiac conduction system.
• A time-ordered propagation of the electrical impulse through the myocardium allows efficient contraction of all four chambers of the heart, starting with the atria pumping the blood toward the ventricles, followed by the ventricles which contribute to the pulmonary and systemic circulation.

• The sinus (sinoatrial) node
• The internodal tracts
• The atrioventricular (AV) node
• The His/AV bundle
• The right and left bundle branches,
• The Purkinje fibers.

• The initial cardiac impulse, produced by pacemaker cells, originates in the sinoatrial (SA) node at the intersection of the right atrium and the superior vena cava.
• This action potential is the trigger of every cardiac cycle, initiating the atrial then ventricular contractions; it is henceforth responsible for the rhythmic beating of the heart.
• This action potential then propagates as a wave of depolarization through the internodal tracts initiating atrial contraction and then converging at the AV node.
  • The convergence occurs because, in a normal heart, the AV node is the only electrical connection between the atria and the ventricles.
  • The conduction of this potential is delayed at the AV node mainly due to the slower depolarization in these cells.
  • This delay is represented as the PR interval of the ECG.
• The electrical impulse then moves to the ventricles by means of the AV or His bundle located in the superior portion of the interventricular septum.
• It then continues moving apically and propagating through both [[]]ventricles via the right and left bundle branches, and the Purkinje fibers.^[1][2][3][4]

• 
  Section of the heart showing the ventricular septum.
• 
  Schematic representation of the atrioventricular bundle of His.

• Similarly to skeletal muscle cells which are also striated muscles, the cardiomyocytes contract in response to a rapid alteration in the cell membrane’s potential.
• However, the cardiomyocytes differ from skeletal muscle cells by three important variations that are essential for cardiac function:
  • 1) They can self-generate a change in cell membrane potential.
  • 2) The action potential can be transmitted directly from cell to cell.
  • 3) The action potentials have a significantly longer duration.

• All cells including cardiomyocytes have a resting membrane potential that is maintained assuming there is no electrical charge crossing the membrane from the intracellular towards the extracellular milieu or vice versa.
• This potential is estimated to be –80 to –90 mV.

• The most crucial ions that determine this resting potential are:
  • Sodium (Na+)
  • Calcium (Ca2+)
  • Potassium (K+)
• Sodium (Na+) and calcium (Ca2+) are most present in the interstitial fluid, while potassium (K+) is more present in intracellularly.

• These ions are lipid insoluble which prevents them from crossing the lipid bilayer or the cell membrane.
• Alternatively, ions cross via specific protein structures in the cell membrane that may be either: ion channels, ion pumps, or ion exchangers.
• These transmembrane proteins are highly specific and allow only one type of ion to pass through which allows good maintenance of the membrane potential.
• Ion channels can be opened, inactivated or closed depending on complex factors that modulate their activity.

• The cardiac contraction action potential is divided into 5 phases.

• The initial rapid increase in the transmembrane potential from -80mV to approximately +30mV constitutes the Phase 0 or the depolarization phase.
• This depolarization results from a rapid increase in the membrane permeability to Na+ ions via opening of voltage-dependent fast Na+ channels allowing Na+ ions to move intracellularly according to their electrochemical gradient.
• Following the conduction of an action potential, a recovery phase is attained where a large number of Na+ channels are inactivated, preventing the conduction of a second action potential.
• When the membrane is fully repolarized, these channels are reactivated and allow the conduction of the following action potential.

• The phase I of the action potential, known as the initial rapid repolarization ensues, resulting from K+ and Cl- ion flux across the membrane.
• This forms the notch seen in the action potential following the depolarization.

• Phase II, almost exclusive to cardiomyocytes, represents a plateau in the membrane potential as an outcome of the equilibrium between Ca2+ influx and K+ outflow.
• The channels responsible for this Ca2+ influx are known as the L-type calcium channels, which are activated rapidly when the membrane potential reaches -50mV, but are slowly inactivated thereafter.
• Throughout this plateau phase, few Na+ channels also remain active.
• These are Na+/Ca2+ exchangers that allow 1 ion of calcium to move outside the cell for every 3 molecules of sodium moving inside the cell.

• The third phase, also known as rapid repolarization, depicts the restoration of a resting membrane potential.
• It is initiated by inactivation of the L-type calcium channels and an increase in K+ outflow.
• This change in potassium across the membrane is related to 3 K+ currents:
  • 1) Inwardly rectifying K+ current (IK1) à Produces the resting membrane potential
  • 2) Transient outward K+ current (ITO) à Accounts for initial part of repolarization
  • 3) Delayed outward K+ current (IK) à Responsible for final part of repolarization

• After repolarization has occurred, intracellular Na+ and extracellular K+ are rearranged via the Na+/K+ ATPase pump.
  • The ATPase moves 3 sodium ions out for every 2 potassium ions moved intracellularly.
• Equilibrium of ions across the membrane is also achieved via the Na+/Ca2+ exchangers.

• The phase IV of the action potential is characterized by a diastolic depolarization that is both spontaneous and slow.
• This phase provides cardiac cells with features of automaticity.
• In a normal functioning heart, only the sinoatrial node is able to reach a threshold potential during phase IV making it the pacemaker of the heart.
• Nevertheless other cells including those in the AV node, the His bundle, and the Purkinje fibers are able to reach a threshold and fire automatically if they are not suppressed by the SA node, which is true in some disease entities.

• Inward Ca2+ current
• Delayed outward K+ current
• IF Currents – Inward sodium-potassium currents activated if membrane repolarizes below the If threshold
• T-type Ca2+ channel – Releases calcium from internal stores

• 1) The slope of diastolic depolarization
• 2) The maximal diastolic potential
• 3) The threshold potential

• All these factors are controlled by the autonomic nervous system allowing for the modulation of the rate of SA node firing and subsequently the heart rate.^[1][5][3][4]

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]

The cardiac action potential is a specialized action potential in the heart, with unique properties necessary for function of the electrical conduction system of the heart.

The cardiac action potential differs significantly in different portions of the heart. This differentiation of the action potentials allows the different electrical characteristics of the different portions of the heart. For instance, the specialized conduction tissue of the heart has the special property of depolarizing without any external influence. This is known as automaticity.

The electrical activity of the specialized conduction tissues are not apparent on the surface electrocardiogram (ECG). This is due to the relatively small mass of these tissues compared to the myocardium.

Intra- and extracellular ion concentrations mmol/L)

Ion	Extracellular	Intracellular	Ratio
Na+	135 – 145	10	14:1
K+	3.5 – 5.0	155	1:16
Cl–	95 – 110	20 – 30	4:1
Ca2+	2	10-4	2 x 104
Although intracellular Ca2+ content is about 2 mM, most of this is bound or sequestered in intracellular organelles (mitochondria and sarcoplasmic reticulum).

Cardiac muscle has some similarities to neurons and skeletal muscle, as well as important unique properties. Like a neuron, a given myocardial cell has a negative membrane potential when at rest. Stimulation above a threshold value induces the opening of voltage-gated ion channels and a flood of cations into the cell. When the threshold is met, an action potential initiates. This causes the positively charged ions to enter the cell [depolarization]. Like skeletal muscle, depolarization causes the opening of voltage-gated calcium channels and entry of Ca²⁺ from the t-tubules. This influx of calcium causes calcium-induced calcium release from the sarcoplasmic reticulum, and the increase in myoplasmic free Ca²⁺ concentration causes muscle contraction. After a delay (the absolute refractory period), Potassium channels reopen and the resulting flow of K⁺ out of the cell causes repolarization to the resting state.

Note that there are important physiological differences between nodal cells and ventricular cells; the specific differences in ion channels and mechanisms of polarization give rise to unique properties of SA node cells, most importantly the spontaneous depolarizations (automaticity) necessary for the SA node’s pacemaker activity.

Major currents

Major currents during the cardiac ventricular action potential

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

Calcium channels

Two voltage-dependent calcium channels play critical roles in the physiology of cardiac muscle: L-type calcium channel (‘L’ for Long-lasting) and T-type calcium channels (‘T’ for Transient) voltage-gated calcium channels.

These channels respond differently to voltage changes across the membrane: L-type channels respond to higher membrane potentials, open more slowly, and remain open longer than T-type channels.

Because of these properties, L-type channels are important in sustaining an action potential, while T-type channels are important in initiating them.

Because of their rapid kinetics, T-type channels respond better to rhythmic stimulation and are also found in some neuron cell bodies, where they play an important role in rhythmic processes such as heartbeat, breathing, and spinal cord pattern generators used in walking.

L-type channels are selectively blocked by dihydropyridines.

Resting membrane potential

The resting membrane potential is caused by the difference in ionic concentrations and conductances across the membrane of the cell during phase 4 of the action potential. The normal resting membrane potential in the ventricular myocardium is about -85 to -95 mV. This potential is determined by the selective permeability of the cell membrane to various ions. The membrane is most permeable to K⁺ and relatively impermeable to other ions. The resting membrane potential is therefore dominated by the K⁺ equilibrium potential according to the K⁺ gradient across the cell membrane. The membrane potential can be calculated using the Goldman equation|Goldman-Hodgkin-Katz voltage equation. The maintenance of this electrical gradient is due to various ion pumps and exchange mechanisms, including the Na⁺-K⁺ ion exchange pump, the Na⁺–Ca²⁺ exchanger current and the I_K1 inwardly rectifying K⁺ current.

Intracellularly (within the cell), K⁺ is the principal cation, and phosphate and the conjugate bases of organic acids are the dominant anions. Extracellularly (outside the cell), Na⁺ and Cl^– predominate.

Phases of the cardiac action potential

The standard model used to understand the cardiac action potential is the action potential of the ventricular myocyte. The action potential has 5 phases (numbered 0-4). Phase 4 is the resting membrane potential, and describes the membrane potential when the cell is not being stimulated.

Once the cell is electrically stimulated (typically by an electric current from an adjacent cell), it begins a sequence of actions involving the influx and efflux of multiple cations and anions that together produce the action potential of the cell, propagating the electrical stimulation to the cells that lie adjacent to it. In this fashion, an electrical stimulation is conducted from one cell to all the cells that are adjacent to it, to all the cells of the heart.

Phase 4

Phase 4 is the resting membrane potential. This is the period that the cell remains in until it is stimulated by an external electrical stimulus (typically an adjacent cell). This phase of the action potential is associated with diastole of the chamber of the heart.

Certain cells of the heart have the ability to undergo spontaneous depolarization, in which an action potential is generated without any influence from nearby cells. This is also known as automaticity. The cells that can undergo spontaneous depolarization the fastest are the primary pacemaker cells of the heart, and set the heart rate. Usually, these are cells in the SA node of the heart. Electrical activity that originates from the SA node is propagated to the rest of the heart. The fastest conduction of electrical activity is via the electrical conduction system of the heart.

In cases of heart block, in which the activity of the primary pacemaker does not propagate to the rest of the heart, a latent pacemaker (also known as an escape pacemaker) will undergo spontaneous depolarization and create an action potential.

The mechanism of automaticity involves the so-called pacemaker channels of the HCN family, Hyperpolarization-gated, Cyclic Nucleotide-gated channels. These poorly selective cation channels conduct more current as the membrane potential becomes more negative, or hyperpolarized. They conduct both potassium and sodium. The activity of these channels in the SA node cells causes the membrane potential to slowly become more positive (depolarized) until, eventually, calcium channels are activated and an action potential is initiated.

Phase 0

Phase 0 is the rapid depolarization phase. The slope of phase 0 represents the maximum rate of depolarization of the cell and is known as V_max. This phase is due to the opening of the fast Na⁺ channels causing a rapid increase in the membrane conductance to Na⁺ (G_Na) and thus a rapid influx of Na⁺ ions (I_Na) into the cell; a Na⁺ current.

The ability of the cell to open the fast Na⁺ channels during phase 0 is related to the membrane potential at the moment of excitation. If the membrane potential is at its baseline (about -85 mV), all the fast Na⁺ channels are closed, and excitation will open them all, causing a large influx of Na⁺ ions. If, however, the membrane potential is less negative, some of the fast Na⁺ channels will be in an inactivated state insensitive to opening, thus causing a lesser response to excitation of the cell membrane and a lower V_max. For this reason, if the resting membrane potential becomes too positive, the cell may not be excitable, and conduction through the heart may be delayed, increasing the risk for arrhythmias.

The fast Na⁺ channel

The fast sodium channel can be modeled as being controlled by a number of gates. Each gate (or gating variable) can attain a value between 1 (fully open) and 0 (fully closed). The product of all the gates denotes the percentage of channels available to conduct Na⁺. Following the model of Hodgkin and Huxley, the sodium channel contains three gates: m, h, and j. In the resting state, the m gate is closed (zero) and the h and j gates are open (one). Hence, the product denoting the percentage of conducting channels is also zero. Upon electrical stimulation of the cell, the m gate opens quickly while simultaneously the h and j gates close more slowly. For a brief period of time, all gates are open (i.e. non-zero) and Na⁺ can enter the cell following its electrochemical gradient. If, as above, the resting membrane potential is too positive, the h or j gates may be considerably less than one, such that the product of m, h and j becomes too small upon depolarization.

Phase 1

Phase 1 of the action potential occurs with the inactivation of the fast Na⁺ channels. The transient net outward current causing the small downward deflection of the action potential is due to the movement of K⁺ and Cl^– ions, carried by the I_to1 and I_to2 currents, respectively. Particularly the I_to1 contributes to the “notch” of some ventricular cardiomyocyte action potentials.

It has been suggested that Cl^– ions movement across the cell membrane during Phase I is as a result of the change in membrane potential, from K⁺ efflux, and is not a contributory factor to the initial repolarisation (“notch”).

Phase 2

This “plateau” phase of the cardiac action potential is sustained by a balance between inward movement of Ca²⁺ (I_Ca) through L-type calcium channels and outward movement of K⁺ through the slow delayed rectifier potassium channels, I_Ks. The sodium-calcium exchanger current, I_Na,Ca and the sodium/potassium pump current, I_Na,K also play minor roles during phase 2.

Phase 3

During phase 3 of the action potential, the L-type Ca²⁺ channels close, while the slow delayed rectifier (I_Ks) K⁺ channels are still open. This ensures a net outward current, corresponding to negative change in membrane potential, thus allowing more types of K⁺ channels to open. These are primarily the rapid delayed rectifier K⁺ channels (I_Kr) and the inwardly rectifiyng K⁺ current, I_K1. This net outward, positive current (equal to loss of positive charge from the cell) causes the cell to repolarize. The delayed rectifier K⁺ channels close when the membrane potential is restored to about -80 to -85 mV, while I_K1 remains conducting throughout phase 4, contributing to set the resting membrane potential.

Abnormal automaticity

The normal activity of the pacemaker cells of the heart is to spontaneously depolarize at a regular rhythm, generating the normal heart rate. Abnormal automaticity involves the abnormal spontaneous depolarization of cells of the heart. This typically causes arrhythmias (irregular rhythms) in the heart.

See also

• Electrical conduction system of the heart
• Action potential
• Antiarrhythmic agents
• Cardiac arrhythmia
• Cardiac pacemaker
• Resting membrane potential
• Ventricular action potential

External links

• Interactive animation illustrating the generation of a cardiac action potential.
• Interactive mathematical models of cardiac action potential and other generic action potentials.

Template:WikiDoc Sources CME Category::Cardiology

• An electrophysiologic study is a term used to describe a number of invasive (intracardiac) and non-invasive recording of spontaneous electrical activity as well as of cardiac responses to programmed electrical stimulation.
• These studies are performed to assess arrhythmias, elucidate symptoms, evaluate abnormal electrocardiograms, assess risk of developing arrhythmias in the future, and design treatment.
• These procedures increasingly include therapeutic methods (typically radiofrequency ablation) in addition to diagnostic and prognostic procedures.
• Other therapeutic modalities employed in this field include antiarrhythmic drug therapy and implantation of pacemakers and implantable cardioverter-defibrillators.

• A specialist in cardiac electrophysiology is known as a cardiac electrophysiologist, or (more commonly) simply an electrophysiologist. Cardiac electrophysiology is considered a subspecialty of cardiology, and in most countries requires two or more years of fellowship training beyond a general cardiology fellowship. They are trained to perform interventional cardiac EP procedures as well as surgical device implantations.

• Ambulatory electrocardiographic monitoring (Holter recording and interpretation; loop recording and interpretation)
• Tilt table testing
• Signal-averaged electrocardiogram (SAECG) interpretation, also referred to as “late potentials” reading
• Electrophysiologic study (EPS)
  • Pacing and recording electrodes are inserted either in the esophagus (intra-esophageal EPS) or, through blood vessels, directly into the heart chambers (intra-cardiac EPS) in order to measure electrical properties of the heart. In addition, intra-cardiac EPS electrically stimulates the heart and induces arrhythmias for diagnostic purposes (“programmed electrical stimulation”).

Electrophysiologists play a role in:

• The initial administration and monitoring of the effect of drugs for treatment of heart rhythm disorders
• The management of severe or life threatening arrhythmias
• The management of arrythmias requiring multiple drugs use

• Ablation therapy is the catheter based creation of lesions in the heart with radiofrequency energy, cryotherapy (destructive freezing), or ultrasound energy in order to cure or control arrhythmias (see radiofrequency ablation). Ablation is usually performed during the same procedure as the electrophysiology study which induces and confirms the diagnosis of the arrhythmia for which ablation therapy is sought.

• It includes ablation for arrhythmias such as: AV nodal reentrant tachycardia, accessory pathway mediated tachycardia and atrial flutter.
• This procedure is usually performed using intracardiac catheters , fluoroscopy (a real-time X-ray camera), and electrical recordings from the inside of the heart.

• It includes ablation for arrhythmias such as: multifocal atrial tachycardia, atrial fibrillation, and ventricular tachycardia.
• In addition to the apparatus used for a “non-complex” ablation, these procedures often make use of sophisticated computer mapping systems to localize the source of the abnormal rhythm and to direct delivery of ablation lesions.

• Implantation of single and dual chamber pacemakers and defibrillators
• Implantation of “biventricular” pacemakers and defibrillators for patients with congestive heart failure
• Implantation of loop recorders (implanted ECG recorders for long term monitoring of ECG to allow for diagnosis of an arrhythmia)
• Clinical follow up and reprogramming of implanted devices

• Mechanism of Arrhythmias
• Diseases of the Conduction System and Bradyarrhythmias
• Narrow Complex Tachycardias
  • Atrial Flutter
  • Atrial Fibrillation
  • Atrial Tachycardia
  • AV Nodal Reentrant Tachycardia
  • Circus Movement Tachycardia
• Wide Complex Tachycardias
  • WPW Syndrome
  • Ventricular Tachycardia
    • Ventricular Tachyarrhythmias in Structurally Normal Hearts
  • Brugada Syndrome
  • Long QT Syndrome
• Ventricular Tachyarrhythmias, Cardiac Arrest and Sudden Cardiac Death
• Arrhythmias in Pregnancy

• Antiarrhythmic Medications
• Indications for Pacemakers
• Indications for an ICD
• Cardiac Resynchronization Therapy
• Catheter ablation

• Clinical cardiac electrophysiology
• Electrical conduction system of the heart
• Electrocardiogram (EKG)
• Basic Principles of ECG Interpretation
• Electrophysiologic study
• Cardiology
• Cardiac arrhythmia

• Cardiac Electrophysiology Society
• Heart Rhythm Society
• International Winter Arrhythmia School

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