Chapter 8 Cardiomyocytes

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    Chapter 8 From Cardiomyocytes

    to Cardiac ConductonBME 501

    T. K. Hsiai

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    1. General Cellular Morphology

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    Cardiac muscle is only in the heart and makes up the atria and ventricles (heart walls). Like skeletalmuscle, cardiac muscle contains striated fibers. Cardiac muscle is called involuntary muscle

    because conscious thought does not control its contractions. Specialized cardiac muscle cells maintain

    a consistent heart rate.

    Over 600 skeletal muscles function for body movement through contraction and relaxation of

    voluntary, striated muscle fibers. These muscles are attached to bones, and are typically under

    conscious control for locomotion, facial expressions, posture, and other body movements. Muscles

    account for approximately 40 percent of body weight. The metabolism that occurs in this large mass-produces heat essential for the maintenance of body temperature.

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    2. Cardiac Cell Muscle

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    Myocardial fibers are separated from adjacent fibers by their

    respective sarcolemmas, the end of each fiber is separated by

    dense structures (intercalated discs), that are continuous with

    the sarcolemma.anatomic syncytium.
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    Adherens Junctions

    Adherens junctions provide strong mechanicalattachments between adjacent cells.

    They hold cardiac muscle cells tightly together as

    the heart expands and contracts.

    They hold epithelial cells together.

    They seem to be responsible for contact inhibition.

    Some adherens junctions are present in narrowbands connecting adjacent cells.

    Others are present in discrete patches holding the

    cells together.

    Adherens junctions are built from:

    cadherins transmembrane proteins (shown in

    red) whoseextracellular segments bind to each other and

    whose intracellular segments bind to

    catenins (yellow). Catenins are connected to actin

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    Gap Junctions Gap junctions are intercellular channels

    some 1.52 nm in diameter. These permit

    the free passage between the cells of ionsand small molecules (up to a molecularweight of about 1000 daltons).

    They are constructed from 4 (sometimes 6)copies of one of a family of atransmembrane proteins called connexins.

    Because ions can flow through them, gapjunctions permit changes in membranepotential to pass from cell to cell.


    The action potential in heart (cardiac)muscle flows from cell to cell through theheart providing the rhythmic contraction ofthe heartbeat.

    Cardiac muscle functions as a syncytium

    as a wave of depolarization followed bycontraction of the entire myoardium in

    Concert (an all-or-none response occurs when

    suprathreshold stimulus is applied to any one

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    Sacrolemmal invaginations at the Z-lines are connected with the bulk

    interstitial fluid, important for excitation-

    contraction coupling.

    MitochondriaRapid oxidation of

    substrates with synthesis

    of ATP for lifetime vs.

    skeletal muscles undergo

    metabolism anaerobically.

    The network of SR consists of

    sarcotubules surrounding the

    myofibrils transport Ca++.

    Colloidal tracer particles

    (2-10 nm) do not enter.

    SR-Ca++ storage

    2.1 Myocyte Internal Structure

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    Cardiac or heart muscle resembles skeletal muscle in some ways: it is striated and eachcell contains sarcomeres with sliding filaments of actin and myosin.

    Cardiac muscle has a number of unique features that reflect its function of pumpingblood:

    The myofibrils of each cell (and cardiac muscle is made of single cells each with asingle nucleus) are branched.

    The branches interlock with those of adjacent fibers by adherens junctions. These strongjunctions enable the heart to contract forcefully without ripping the fibers apart.

    Cardiac Muscle
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    The Muscle Fiber

    The striated appearance of the muscle fiber is created by a pattern of alternatingdark A bands and light I bands.

    The A bands are bisected by the H zone

    The I bands are bisected by the Z line.

    Each myofibril is made up of arrays of parallel filaments.

    The thick filaments have a diameter of about 15 nm. They are composed of the protein myosin.

    The thin filaments have a diameter of about 5 nm. They are composed chiefly of the protein actin along with

    smaller amounts of two other proteins: troponin and tropomyosin.
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    Bo-Inspired Micro-Electrostatic actuators

    Principle of comb-drive actuation

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    Regulation of Muscle Contraction

    The main feature of muscle contraction

    is the interaction of actin, myosin and ATP.

    This fundamental process of contraction is

    regulated by the tropomyosin(TM)-troponin-Ca2+

    system. According to the current theory, in

    the resting muscle TM is positioned in thegroove of the actin double helix in a way

    that it sterically blocks the combination of

    myosin with actin. This is illustrated in figure, which

    shows a thin filament composed

    of actin, tropomyosin(TM), TN-C(troponin), TN-I,

    and TN-T.

    In the absence of Ca2+ (relaxed state), TM blocks the

    cross-bridge binding sites on actin. Binding of Ca2+

    to TN-C (activated state) initiates the TM movement,

    through TN-T, from the center of the actin strand to its

    side, thereby releasing the steric blocking. In addition,the TN-C-Ca2+ complex removes TN-I from its

    inhibitory position on actin; thus the combination of

    the myosin head with actin can proceed to full extent.

    Since in the thin filament there is only one TN and

    one TM molecule per seven G-actin molecules, one

    has to assume that cooperative interactions play a

    major role in the regulation of contraction.

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    4. Cardiac Muscle Electrical Activity

    Length-tension relationship of a single frog semitendinosus

    muscle fiber (From Gordon et al., 1966). The numbers 1

    through 4 on the length tension curve correspond to the

    numbers on the schematic diagram of thick and thin filament

    arrangement. In this way the relationship between thick and

    thin filaments can be compared to the tension at various

    sarcomere lengths.

    Crossbridge cycle and its relation to actomyosin ATPase

    With a new ATP a new cycle may begin

    and the cycling may continue until theregulatory mechanism stops the

    interaction of actin and myosin. As

    shown in Fig. ME4, ATP is needed for

    step 1; that is for the detachment of

    myosin from actin. In case of ATP

    depletion, the cycle is arrested. When

    actin and myosin are permanently bound

    in the absence of ATP, the muscle

    becomes rigid.

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    Length-tension relationship: The physiological interpretation of the sliding filament theory was tested by measuring

    the tension of a single muscle fiber at different sarcomere length (Gordon et al., 1966). Figure illustrates the

    experiment. Maximum tension was obtained at rest length, between 2.0-2.25 micron, when all crossbridges were

    in the overlap region between thick and thin filaments. When the muscle fiber was stretched so that the

    sarcomere length increased from 2.25 to 3.675 micron and consequently the number of crossbridges in the

    overlap region decreased from maximum to zero; the tension fell from 100% to 0.The crossbridges are uniformly distributed along the thick filaments with the exception of a short bare zone in the

    middle. The crossbridges seem to be identical and are the site of the interaction between thick and thin

    filaments. The tension is the algebraic sum of the tension produced at each individual site. At or above rest

    length the tension is directly proportional to the number of crossbridges in the overlap region between thick and

    thin filaments.

    Below rest length, when the thin filaments meet in the center of the A band or they start to interact with the

    oppositely directed crossbridge sites past the bare zone (in the middle of the sarcomere), tension drops off.

    Crossbridge cycle and its relation to actomyosin ATPase: A scheme for the coupling of ATP hydrolysis to the

    crossbridge cycle is shown in Figure. The following major steps are involved:

    -ATP dissociates actomyosin into actin and myosin; i.e. the thick filaments will be detached from the thin

    filaments. ATP binds to the myosin head in the thick filaments.

    -ATP is hydrolyzed by myosin; the products ADP and Pi are bound to myosin. The energy released by the

    splitting of ATP is stored in the myosin molecule. The myosin.ADP.Pi complex is a high-energy state; this is

    the predominant state at rest.-Upon muscle stimulation, the inhibition of actin-myosin interaction, imposed by the regulatory proteins, is lifted

    and consequently the myosin with bound ADP and Pi attaches to actin. It is believed that the angle

    of crossbridge attachment is 90o.

    -The actin-myosin interaction triggers the sequential release of Pi and ADP from the myosin head, resulting in

    the working stroke. It is thought that the energy stored in the myosin molecule brings about a

    conformational change in the crossbridge tilting the angle from 90o to 45o. This tilting pulls the actin filament

    about 10 nm toward the center of the sarcomere, while the energy stored in myosin is utilized.

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    4. Cardiac Muscle Electrical Activity

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    The Equilibrium Potential is Predictable - The Nernst Equation

    The equilibrium described above is predictable with the Nernst equation, which here is given in a form applicable to

    cell membranes:


    Ex is the Nernst potential for ion X (measured as for membrane potentials

    inside with respect to outside)

    [X]o is the concentration of X outside the cell

    [X]i is the concentration of X inside the cell

    zx is the valence of ion X

    R is the gas constant

    T is the absolute temperatureF is Faraday's constant


    Vm = 60 log -------- mV


    The Nerst Equation for individual ions

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    Relative Intra- and Extracellular Concentrations of Some Important Ions


    Ion Intracellular (mM) Extracellular (mM)

    Na+ Low (15) High (145)

    K+ High (150) Low (4)


    low (0.07) high (2)

    E (mV)




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    Overall potential: Goldman-Hodgkiom-Katz Equation

    Vm is the membrane potential. This equation is used to determine the resting membrane potential in real cells, in which K+,

    Na+, and Cl- are the major contributors to the membrane potential. Note that the unit of Vm is the Volt. However, the

    membrane potential is typically reported in millivolts (mV). If the channels for a given ion (Na+, K+, or Cl-) are closed, then the

    corresponding relative permeability values can be set to zero. For example, if all Na+ channels are closed, pNa = 0.

    R is the universal gas constant (8.314 J.K-1.mol-1).

    T is the temperature in Kelvin (K = C + 273.15).

    F is the Faraday's constant (96485 C.mol-1).

    pK is the membrane permeability for K+. Normally, permeability values are reported as relative permeabilities withpK havingthe reference value of one (because in most cells at rest pK is larger than pNa and pCl). For a typical neuron at rest, pK : pNa

    : pCl = 1 : 0.05 : 0.45. Note that because relative permeability values are reported, permeability values are unitless.

    pNa is the relative membrane permeability for Na+.

    pCl is the relative membrane permeability for Cl-.

    [K]o is the concentration of K+ in the extracellular fluid. Note that the concentration units for all the ions must match.

    [K]i is the concentration of K+ in the intracellular fluid. Note that the concentration units for all the ions must match.

    [Na]o is the concentration of Na+ in the extracellular fluid. Note that the concentration units for all the ions must match.

    [Na]i is the concentration of Na+ in the intracellular fluid. Note that the concentration units for all the ions must match.

    [Cl]o is the concentration of Cl- in the extracellular fluid. Note that the concentration units for all the ions must match.

    [Cl]i is the concentration of Cl- in the intracellular fluid. Note that the concentration units for all the ions must match.


    Universal Gas Constant (R) = 8.314 J.K-1.mol-1

    Faraday's Constant (F) = 96485 C.mol-1

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    Membrane: patch clamping

    Biological membranes are fluid mosaics of the lipids and proteins.

    The lipids are arranged as bilayers and the proteins are generally free to diffuse laterallyin the lipid matrix. The function of the membranes are mediated by the integral

    membrane proteins that serve as channels, receptors, and energy transducers.

    Ion channel

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    Methods to study cardiac action potential

    Electric cardiac cycle

    Patch clamping (ion channels) Action potential of skeletal, smooth muscles,and nerves (two electrodes: reference and detection)


    b c d eERP RRP


    difference= -90 mV

    0 mV

    Phase 0: rapid


    Phase 1: partial repolarization

    Phase 2: plateau

    Phase 3: more negative


    Phase 4:

    Resting state


    ~20 mV

    0.1-0.2 s

    Resting state

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    SA node (slow

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    Atrial and ventricular cells (fast response)

    Rapid depolarization

    Increased sodium permeability(INa inward current)

    Brief repolarizationDue to transient outward current

    of potassium ions (Ito)

    Plateau phaseA delicate balance between small

    inward and outward currents:

    Outward current mediated by activation of

    Potassium conducting ionic channel (Ik)

    Inward current by slow calcium current (I Ca)

    Repolarizationto the resting state.

    -slow inward Ca++ current

    -outward K+ current (I KI)

    -Sodium-potassium pump

    (Ip=Na+-K+ ATPase pump)



    Diastolic portionof the action potentialNo spontaneous diastolic

    depolarization occurs due to

    the activation of K current

    (the inward rectifier, I KI)

    Threshold level


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    Cardiac action potential

    (fast response)


    ~-65 mV

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    Nodal cells (slow response)

    Phase 0Activation of calcium channel

    (Ca++ in flux (ICa++))

    Phase 2

    Phase 3

    Phase 4-In the nodal cells, IKI is not


    -spontaneous diastolic

    depolarization occurs as a

    results of the activation of the

    pacemaker current (If)

    Normal automaticity in the nodal cells is the net result of the absence of Ik1 andthe presence of If.

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    Ionic Basis of Action Potential

    a) Electrical Phenomena & Ionic Fluxes

    Resting Membrane & Action Potentials

    there is a concentration (chemical) gradient of ions across the cellmembrane down which ions flow

    ion distribution establishes an electrical gradient ie. interior of the cell isnegative relative to the exterior

    the distribution of ions across the cell membrane and the nature of thismembrane explain the membrane potential

    membrane potential determined by Na+, K+, Ca2+ on either side of themembrane and the permeability of the membrane to each ion

    ions diffuse through membranes via ion-specific channels flux of ions controlled by ion-specific "gates"

    gates are opened and closed by specific transmembrane conditions(voltage, ionic or metabolic)

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    Resting Membrane Potential

    the resting membrane potential (steady potential) of cardiac cellsis - 90 mV (ie. inside is negative)

    this is maintained by the Na+-K+ ATPase which pumps K+ back into

    the cell and keeps intracellular Na+ concentration low passage of electrical current through the membrane leads to

    decreases resting membrane potential threshold potential~65 mV

    in cardiac muscle cells, stimulation triggers a voltage-dependentincrease in Na+ channels that initiates contraction

    this allows cells to generate self-propagating impulses that are

    transmitted along their membranes for great distances transmembrane action potential of single cardiac muscle cells is

    characterized by rapid depolarization, a plateau, and slowrepolarization

    ie. Na+rapidly enters cells at the start of action potential

    Ca2+ enters and K+ leaves the cell with each action potential

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    IKI Ca++I Ca++



    Nodal cells

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    hases of the action potential of a cardiac muscle fiber

    1) depolarization proceeds rapidly due to Na+ influx through rapidly openingNa + channels

    2) plateau phase is due to Ca2+ influx through more slowly opening

    Ca + 2 channels

    3) repolarization is due to closure of Ca2+ channels, K+ efflux through K+ channels

    4) transmembrane potential and ion gradients are restored by sodium pump

    (Na + -K + ATPase=Ip)

    One of the K channel is ATP sensitive.The KATP channel normally is inactive during physiologicConditions (the channel is inhibited by ATP under physiologic

    Conditions). Under conditions such as ischemia or hypoxia, the

    channel is activated when the intracellular ATP concentration

    is decreased.

    Duration of the action potential is affected

    by changes in Ca 2+ and/or K+ conductance

    during repolarization. Activation of K+ will

    shortened the duration of action potential. But

    the duration of activation potential prolonged

    when the outward-going K+ are inhibited


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    The cardiac action potential

    The cardiac action potential is the fundamental unit of electrical activity in the heart. ominant ion

    currents that contribute to the action potential in a myocyte from the ventricle are shown in the

    previous page.

    -Initial depolarization (phase 0) is generated by rapid influx of sodium ions (INa), whose positive

    charge depolarizes the membrane toward more positive potentials.

    -Once depolarized, the membrane repolarizes transiently due primarily to potassium ion efflux (Ito) toform a notch in the contour of the action potential (phase 1).

    -The membrane remains depolarized during the plateau phase (phase 2) , where net current flux is

    small, resulting from a near balance of positive charges moving inward (carried predominantly by

    calcium ions, ICa, with a smaller component contributed by a persistent sodium influx) and positive

    charges moving outward (carried predominantly by two components of the delayed rectifier potassium

    current, one that activates rapidly, IKr, and the other that activates slowly, IKs). The inward calcium

    current mediates additional calcium release from stores within myocytes and activates the contractile

    machinery during mechanical systole. With time, outward potassium currents dominate residual

    inward calcium and sodium currents, and the efflux of positive charge allows the membrane to

    repolarize to its resting potential (phase 3), from which it is soon ready for the next heartbeat.

    -In myocardial cells, such as sinoatrial nodal cells and atrioventricular nodal cells, a pacemaker

    current (If) mediates gradual membrane depolarization (phase 4) until a threshold potential is reached

    that triggers phase 1 and the ensuing heartbeat.

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    Excitation-Contraction Coupling

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    Mechanistically, digoxin inhibits the Na/K ATPase pump. Digoxin probably competes with potassium for the K binding site

    on the pump. Referring back to the basic physiologic function of a myocardial cell, recall that this pump exchanges

    intracellular Na for extracellular K. Also recall that extracellular Na is exchanged for intracellular Ca by a non-energy

    dependent facilitated diffusion countertransport mechanism. THEREFORE, if the Na/K pump is inhibited, intracellular Na

    will INCREASE. This obliterates the concentration gradient that drives the Na/Ca exchange mechanism. This, in turn,

    results in an increase in intracellular Ca. This Ca may then be used to directly or indirectly (by causing the release ofadditional Ca from the SR) cause prolonged excitation-contraction coupling, thereby prolonging the contraction of the

    muscle fibres (hence a positive inotropic effect).

    The mechanism, illustrated and discussed above, is responsible for the beneficial pharmacodynamic response of positive

    inotropy. However, cardiac glycosides possess other pharmacodynamic actions that contribute other effects that may also

    influence cardiac function.These agents will stimulate both the adrenergic and vagal neurones that control cardiac function. Stimulation of these

    nerves is presumed to result from a similar action on the neurone (inhibition of ATPase). These effects are somewhat dose

    dependent, with myocardial tissues affected at low doses, the vagus nerve affected at slightly higher doses, and

    sympathetic stimulation not clinical evident until toxic doses are attained.

    Recalling the normal physiology of cardiac control, it is evident that stimulation of the vagus nerve at therapeutic doses of

    digoxin can result in a negative chronotropic effect, slowing heart rate (bradycardia). Excessive action by this mechanism

    can ultimately result in second or third degree heart block that may be characterisic of digoxin toxicity. (Another contributor

    to this bradycardia is the effect of digoxin at the AV node specifically, where the refractory period may be prolonged,

    delaying impusle conduction from the AV node to the ventricle.)

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    a, Typical action potential (Em), Ca2+ transient ([Ca2+]i),

    and calculated INa/Ca reversal potential (ENa/Ca).

    b, Curves illustrating how submembrane [Na+]i and


    ]i ([Na+

    ]sm and [Ca2+

    ]sm) might change during theaction potential owing to local diffusion limitations (note

    that [Ca2+]sm may be lower than that in the cleft,

    [Ca2+]cleft, as shown in d).

    c, INa/Ca calculated by the equation given in ref. 25 as a

    function of Em and the indicated concentrations of Ca2+

    and Na+. Right panel is expanded in time.

    d, Geometry of junctional and submembrane spaces.
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    Action potential configurations in different regions of the mammalian heart.

    Electrocardiogram (ECG)

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    g ( )

    The electrocardiogram (ECG) is a

    technique of recording bioelectric

    currents generated by the heart.

    Clinicians can evaluate the

    conditions of a patient's heart from

    the ECG and perform further

    diagnosis. ECG records are obtained

    by sampling the bioelectric currents

    sensed by several electrodes, known

    as leads. A typical one-cycle ECG

    tracing is shown above.

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    SA node (slow

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    El i l C di

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    Electrical Cardiogram



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    An ECG is printed on paper covered with a grid of squares. Notice that five small squares on the paper form a larger square. The width of a single small

    square on ECG paper represents 0.04 seconds. The first little hump is known as the P wave. It occurs when the atria depolarize (i.e. trigger). The next

    three waves constitute the QRS complex. They represent the ventricles depolarizing. These three are lumped together because a normal rhythm may not

    have all three. Many times, you'll only see a R and an S. This is not abnormal. If there are less than three, how do we know which one is which? Well, the

    R wave is the first wave ABOVE the isoelectric line. You then name the waves in relation to the R wave. If it falls before the R wave, it is called the Q wave;

    after the R wave is the S wave.

    An electrocardiogram (ECG) is a record of the electric activity of the heart A

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    The electrocardiogram (ECG or sometimes called EKG) is a record of the heart's electrical activity obtained from a standard set of

    body surface electrodes and presented to the physician as the "12-lead ECG": that is, 12 independent graphs of voltage vs. time asobtained from the electrodes.

    Current ECG

    practice. Although

    cardiac activity is

    inherently 3-

    dimesional, the

    current ECG

    presents data in

    only 2 dimensions,

    resulting in loss of



    An electrocardiogram (ECG) is a record of the electric activity of the heart. A

    standard ECG is produced by sensing electric potentials in six leads from the

    limbs (I, II, III, aVR, aVL, aVF) and six leads from the chest (V1-V6).

    Electric signals of the heart spread in all directions. However each standard

    lead can accurately represent only a small spatial sector around its axis (axes

    are shown as green arrows). When projected onto an imaginary sphere

    surrounding the heart, such a conic sector would look like a small circle or an


    When an ECG is taken, twelve standard ECG leads may produce normal

    tracings (gray ovals) while a pathologic focus (black spot) may remainunnoticed. This happens, because electric signals (red arrow) from the

    pathologic focus do not propagate along (are not collinear with) the axes of

    any of standard ECG leads and therefore their magnitude does not reach

    diagnostic thresholds to be properly detected. In such cases a correct

    diagnosis is missed.

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    Signal Processing

    The signal from the body is being amplified(the signals from the

    body are small and weak, ranging from 0.5 mV to 5.0 mV),

    filtered (to remove the noise), sampled (by sampling I mean it

    goes to an Analog to Digital converter aka ADC) and then sent to

    your computer through RS232 (wireless or any other way but

    RS232 was chosen because it is the simplest and fastest to


    Data acquisition or where the signal of interest is represented by

    a small voltage fluctuation superimposed on a voltage offset are

    called instrumentation amplifiers. Instrumentation amplifiers have

    a high CMRR(Common Mode Rejection Ratio) which means they

    have the ability of a differential amplifier to not pass (reject) the

    portion of the signal common to both the + and inputs.

    The noise comes from muscle contractions, power lineinterference 50-60 Hz, electrode contact noise, noise from other

    electronic devices and etc. The filter for the ECG application

    should be a notch filter(high-pass and low-pass filter). It should

    filter in the range from 0.5 Hz to 50 Hz.

    A l d lt 12 l d ECG

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    A normal adult 12-lead ECG

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    Normal intracardiac recording

    Normal intracardiac recording. Surface ECG leads I, II, and V1 are displayed with intracardiac ECGs from the high right

    atrium (HRA), left atrium from the coronary sinus (CS), and AV junction to obtain a His bundle electrogram (HBE). T, time

    lines; A, atrial activation; H, His bundle activation; V, ventricular activation. Atrial activation begins in the HRA and spreads

    inferiorly to the low atrial septum, as recorded in the HBE, and the left atrium, as recorded in the CS. The AH and HV

    intervals represent AV nodal and His-Purkinje conduction times, respectively. Vertical lines = 0.10 s.

    Intracardiac electrograms. Schematic illustrations of several intracardiac electrograms contrasted with a conventional body-

    surface electrocardiogram (ECG). HRA = high right atrial electrogram; HBE = His bundle electrogram, in which A = low

    right atrial activity, H = His bundle activity, and V = ventricular septal activity; also shown are the P R, PA, AH, and HV


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    Biventricular Pacing for Heart Failure- Cardiac resynchronization therapy (CRT)LVEF 35 MM, NYHC III or IV

    Biventricular pacing for cardiac resynchronization


    -The right atrial and right ventricular pacing leads are

    inserted in the usual manner.

    -The left ventricular pacing lead is inserted via thecoronary sinus and advanced into a cardiac vein on the

    lateral wall of the left ventricle.

    -The location and accessibility of a suitable vein differ

    from one patient to another, because of variability in the

    coronary venous anatomy.

    Summary: Cardiac Conduction System

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    y y

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    Sequence of Cardiac Conduction