Cardiac Electrophysiology

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Cardiac Electrophysiology
W. J. Lederer Director Medical Biotechnology
Center Room 340 MBC Building 725 W. Lombard
Street telephone [phone] email
lederer_at_umbi.umd.edu
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Cardiac Electrophysiology

• Overview Electrical Activity in the normal
  heart
• Voltage-activated membrane currents
• The conducted Action Potential
• How Pacemaker activity arises
• Action Potential in ventricular muscle

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Overview Electrical Activity in the normal heart
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Terms
action potential or "AP" stereotyped voltage
change with time depolarize make voltage more
positive hyperpolarize make voltage more negative
repolarization
depolarization
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Channel-types
voltage-gated channels channels that open or
close in response to changes in membrane
potential. Central to the AP and conducted AP.
ligand-gated channels channels that open or
close in response to a drug, neurohormone, etc.
We will discuss later.
"background" channels channels that are NOT
voltage-gated and NOT ligand gated. Generally
they are open. Important to set "resting" or
"diastolic" potential.
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Membrane currents that underlie the cardiac AP
Voltage-gated Channels of interest to us Na
(INa) Ca2 (L-type T-type) ICa,L and
ICa,T K (rapid, slow, transient outward)
IKR, IKS, ITO) Both Na and K ("funny")
IF Transporter N/Ca2 exchanger INCX
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Effect of channels opening
1. When channel is closed, no current flows
through channel 2. When cations () enter cell
("inward current"), cell depolarizes (becomes
more positive inside)
1. When channel is closed, no current flows
through channel 2. When cations () enter cell
("inward current"), cell depolarizes (becomes
more positive inside) 3. When cations () exit
cell ("outward current"), cell polarizes
(becomes more negative inside)
The effect of the opening of a particular kind of
channel on the cardiac AP depends on 1. The
permeant ion (e.g. Na, Ca2, K, etc) 2. The
Nernst potential for "X", the relevant ion,
(EX) 3. The membrane potential (VM) when the
channels open 4. When VM is negative to EX, there
is inward (depolarizing) current 4. When VM is
positive to EX, there is outward (repolarizing)
current
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Nernst potential for ions in heart
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Nernst Potential for Ion "X"
R"gas constant" Ttemperature (o
K) Zvalence FFaraday ?105 Coulomb/Mole
For a positive monovalent ion
if Ko were 1 mM and Ki were 100 mM then EK -120
mV
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AP and "Nernst" or "Reversal" Potentials
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Phases of the Cardiac Action Potential (AP)
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Comparison of APs
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Currents in the heart
repolarizing potassium currents "IK"
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Genes for key channels
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Purpose of currents
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Electrical Activity in the heart
pacemaker
SA Node
Ventricular Muscle
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The Conducted Action Potential (AP)
AP originates in SA node and is conducted through
atria through AV node to His-Purkinje fiber
system through ventricular muscle. For this
discussion we first examine a region of
ventricular muscle just before the AP arrives....
Before AP arrives
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The Conducted Action Potential (AP)
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The Conducted AP
When the AP is very far away from point "B" the
intracellular resistance is very high and there
is little effect of the AP on the voltage at "B".
As the AP approaches "B" the depolarizing effect
of the AP increases until the threshold potential
is reached and a "regenerative" AP is produced at
"B"
AP is being conducted from left to right
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AP propagation is slower when....

• There is less inward current
• fewer Na channels activated (V or A muscle).
  Example following use of Na channel blocking
  antiarrhythmics.
• fewer Ca2 channels activated (SA or AV node).
  Example following use of Ca2 channel blockers.
  
• The threshold for the regenerative AP is more
  positive. Example following use of Na or Ca2
  channel blockers.

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AP conduction velocity in different tissues

• Depends on which currents are activated and how
  much
• Fastest Purkinje fibers - largest number of Na
  channels. Many Ca2 channels.
• Fast V and A muscle - large number of Na
  channels. Many Ca2 channels.
• Slowest SA and AV node. No Na channels. Ca2
  channels underlie conducted AP. More than enough
  Ca2 channels.

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Conduction velocity in different tissue
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What is Vm when multiple channels are activated?
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GKH Goldman-Hodgkin-Katz
R"gas constant" Ttemperature (o K) FFaraday
?105 Coulomb/Mole PX permeability of ion "X"
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Chord Conductance
gX conductance of ion "X" EX Nernst potential
of ion "X"
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Action potential Balance of Current

• More inward current Cell depolarizes
• Less outward current Cell depolarizes

• More outward current Cell hyperpolarizes
• Less inward current Cell hyperpolarizes

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APs in heart

• No phase 4 depolarization
• conducted AP triggers AP in tissue -- if no
  conducted AP, no AP occurs
• maximum diastolic potential -80 to -90 mV

• Large phase 4 depolarization
• spontaneous AP's set heart rate
• maximum diastolic potential about -65 mV

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SA Node

• Normal pacemaker
• Intrinsic rate of 60 beats per minute
• No Na current
• Ca2 current underlies upstroke
• Ca2 current underlies conducted AP

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How does a pacemaker develop spontaneous activity?
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Pacemaker Activity in SA node
pacemaker depolarization
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Ca2 current in SA node
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Properties of ICa
voltage
current
inactivation (recovery from inactivation)
activation (deactivation)
ICa shows "inactivation" This means that after
the current is activated by a depolarized
voltage, and the "activation" is maintained by
the continued depolarization, the current
decreases with time.
ICa shows recovery from "inactivation" This
means that after the current is de-activated by a
repolarized voltage, it still takes time before
the effect of "inactivation" is removed.
In SA node, ICa remains slightly activated at the
maximum diastolic potential (MDP) of -65
mV This means that during phase 4 in the SA
node, recovery from inactivation produces a
growing inward current!
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Repolarizing K currents in SA node
deactivation takes place slowly for the
repolarizing K currents
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F current in SA Node

• activated slowly by hyperpolarization
• produces inward (depolarizing) current because
  the "reversal" potential of IF (-35 mV) is
  positive to Vm

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Pacemaker depolarization in SA node depends on
K, F and Ca currents
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Normal pacemaker depolarization in heart

• SA node as discussed
• AV node similar to SA node but lower rate
• Purkinje fibers
• F current is the only pacemaker current
• Very slow intrinsic rate (20 per min. or less)

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Ventricular Muscle has no pacemaker depolarization
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Ventricular AP depends on Na, Ca and K currents
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Modulation of AP properties by adrenergic and
cholinergic systems
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Cardiac Electrophysiology

• Overview Electrical Activity in the normal
  heart
• Voltage-activated membrane currents
• The conducted Action Potential
• How Pacemaker activity arises
• Action Potential in ventricular muscle