Cardiac Electrophysiology

1

2

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

OVERVIEW: ELECTRICAL ACTIVITY IN THE NORMAL HEART

3

4

Terms

5

action potential or "AP": stereotyped voltage change with timedepolarize: make voltage more positivehyperpolarize: make voltage more negative

Action potential from a heart cell

depolarization

-80 mV

+60 mV

300 ms

repolarization

6

Channel-types

Voltage-gated channels: channels that open or close in response to changes in membrane potential. Central to the AP and conducted AP.

"Background" channels: channels that are NOT voltage-gated and NOT ligand gated. Generally they are open. Important to set "resting" or "diastolic" potential.

Ligand-gated channels: channels that open or close in response to a drug, neurohormone, etc. We will discuss later.

voltage-gated

background

7

Membrane currents that underlie the cardiac AP

heart cell

Voltage-gated Channels of interest to usNa+ (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

TransporterN+/Ca2+ exchanger INCX

8

Effect of channels opening1. When channel is closed, no current flows through channel 2. When cations (+) enter cell ("inward current"), cell depolarizes

(becomes more positive 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 open4. When VM is negative to EX, there is inward (depolarizing) current 4. When VM is positive to EX, there is outward (repolarizing) current

depolarizinginward (+) current

+repolarizingoutward (+) current

+

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)

9

Nernst potential for ions in heart

-41

Nernst Potential for Ion "X"

10

i

o

i

o

][X

][Xlog

ZF

2.3RT

][X

][Xln

ZF

RT

X

X

E

E

EX = 60 mV log ([X+]o/[X+]i).if Ko were 1 mM and Ki were 100 mM then EK = -120 mV

i

o

i

o

][X

][Xlog

ZF

2.3RT

][X

][Xln

ZF

RT

X

X

E

E

For a positive monovalent ion

R="gas constant"T=temperature (o K)Z=valenceF=Faraday 105 Coulomb/Mole

11

AP and "Nernst" or "Reversal" Potentials

-80 mV

+60 mV

-97EK - Nernst potential for K+ = "reversal" potential

-37EF or ECl

+ 70ENa

+124 ECa

time

volt

ag

e

12

Phases of the Cardiac Action Potential (AP)

-80 mV

+60 mV

Phase 0(upstroke)

Phase 2 (plateau)

Phase 1 (early repolarization)

Phase 4 (diastole)

Phase 4 (diastole)

Phase 3 (repolarization)

13

Comparison of APs

pacemakerdepolarization

spontaneousdepolarization

No pacemakerdepolarization

conducted APto cell triggersdepolarization

No pacemakerdepolarization

conducted APto cell triggersdepolarization

AP from VENTRICULAR MUSCLE

-80 mV

-80 mV

0

maximumdiastolic potential

AP from ATRIAL MUSCLE

AP from SA node or AV node

14

Currents in the heart

repolarizing potassium currents = "IK"

15

Genes for key channels

16

Purpose of currents

17

Electrical Activity in the heart

SA Node

VentricularMuscle

pacemaker

18

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

1. The AP is being conducted from the left to the right (in this example)

3. The "voltage-gated" ion channels in the SL (sarcolemma) are responsible for the AP.

voltage-gate

4. Gap junction channels between the heart cells are always open and permit the AP to be conducted from cell to cell. Current can flow.

gap junctions

cell A cell B cell C cell D cell E cell F cell G

2. The resting potential of the heart cells is negative (between -80 and -90 mV) controlled by "background" ion channels (i.e. NOT voltage-gated).

-90 mV -90 mV-90 mV -90 mV -90 mV -90 mV -90 mV

19

The Conducted Action Potential (AP)

AP is being conducted from left to right

BA

negative = inward = depolarizing current

distance time

volt

age

VATime

VBTime

VB-VA

0

+

-

Time

current flowing into region "B" from region "A" is given by Ohm's law:

IAB = (VB-VA)/RAB

IAB is proportional to (VB-VA)

RAB is the resistance between "A" and "B"

20

The Conducted APWhen 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".

6

6

7

7

5

5

2

2

3

3

4

4

1

1

B

THRESHOLD FOR REGENERATIVEAP 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

volt

age

time

(Right) Plot of VB as a function of time as the propagated AP approaches "B"

21

AP propagation is slower when....

• There is less inward current

1. fewer Na+ channels activated (V or A muscle). Example: following use of Na+ channel blocking antiarrhythmics.

2. 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.

22

AP conduction velocity in different tissues

• Depends on which currents are activated and how much

1. Fastest: Purkinje fibers - largest number of Na+ channels. Many Ca2+ channels.

2. Fast: V and A muscle - large number of Na+ channels. Many Ca2+ channels.

3. Slowest: SA and AV node. No Na+ channels. Ca2+ channels underlie conducted AP. More than enough Ca2+ channels.

23

Conduction velocity in different tissue

very slow

fast

very fast

24

What is Vm when multiple channels are activated?

GKH = Goldman-Hodgkin-Katz

25

oCliNaiK

iCloNaoKm

][ClP][NaP][KP

][ClP][NaP][KPln

F

RT V

R="gas constant"T=temperature (o K)F=Faraday 105

Coulomb/MolePX = permeability of ion "X"

Chord Conductance

26

ClE

Clg

Nag

Kg

Clg

NaE

Clg

Nag

Kg

Nag

KE

Clg

Nag

Kg

Kg

Vm

gX = conductance of ion "X"EX = Nernst potential of ion "X"gX

gK + gNa + gCl

is the fraction of the total conductance due to ion "X"

27

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

28

AP’s 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

29

SA Node

•Normal pacemaker

•Intrinsic rate of 60 beats per minute

•No Na+ current

•Ca2+ current underlies upstroke

•Ca2+ current underlies conducted AP

30

How does a pacemaker develop spontaneous activity?

31

Pacemaker Activity in SA node

pacemaker depolarization

32

Ca2+ current in SA node1. Recovery from

inactivation2. Some

background Ca current activation at –65 to –60 mV

33

Properties of ICa

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!

voltage

currentinactivation(recovery from inactivation)

activation(deactivation)

34

Repolarizing K+ currents in SA node

decreasing outward current

deactivation takes place slowly for the repolarizing K currents

35

“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

36

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

37

Normal pacemaker depolarization in heart

• SA node• AV node – similar to SA node but lower rate • Purkinje fibers

1. “F” current is the only pacemaker current2. Very slow intrinsic rate (20 per min. or less)

38

Ventricular Muscle has no pacemaker depolarization

RRP= relative refractory period

ERP= effective refractory period

ERP due to mainly Na+ channel inactivation

39

Ventricular AP depends on Na, Ca and K currents

INa

ICa

IK

40

Modulation of AP properties by adrenergic and cholinergic systems

THANK YOU

41