Cardiac Electrophysiology II: Pacemaker Cells

Question 1

Answer 1

Sinus Node

• higher resting potential
• unstable baseline (pacemaker function)
• slower rate of rise (slow conduction due to Ca channels)

Atrial Muscle

• higher amplitude
• faster rate of rise

Example of heterogenous localization

Question 2

What are the inherent characteristics of pacemaker cells?

Why is the SA node the dominant pacemaker cell? How does the speed of discharge compare to the speed of conduction of this node?

What are characteristics of potential pacemakers? What cells have this ability to take over?

Answer 2

Characteristics of pacemaker cells
unstable membrane potential
rhythmicity

_SA node - dominant_
fastest rhythm (discharge rate)
slowest conduction

Potential (subsidiary) pacemakers

• slower inherent discharge
• usually suppressed but virtually all cells can take over if needed…or not (bad)

Question 3

What are the intrinsic rates of the following potential pacemaker cells?

Which pacemaker cells have the fastest and slowest conduction rates?

Answer 3

SA node
fastest rate, slowest conduction

Purkinje system
slowest Rate, fastest conduction

Question 4

Describe overdrive suppression in simplistic terms.

What is the main transporter involved in this mechanism?

Describe the mechanism in steps.

Answer 4

Overdrive suppression - hyperpolarizing cells “below” it so they are less excitable, taking over control of rhythm

Na/K ATPase huge role

• SA node driving cells at 70
• Purkinje wants to go at 25 - faster than they want - accumulate sodium
• as sodium accumulates Na/K ATPase upregulates - bringing more potassium in, hyperpolarizing

Question 5

What etiologies can cause loss of SA node drive?

What occurs when this driving force of contraction is lost?

What is down regulated?

What is in charge of contraction then?

Answer 5

Loss of SA node drive

etiologies: SA block, AV block, sinus arrest, etc…
- hyperpolarizing current lost (Na/K ATPase downregulates)
- spontaneous depolarization at next cell’s intrinsic rate
- potential pacemaker can take over

Question 6

What is a scary thing that occurs between loss of SA node drive and takeover of other conducting cells?

Answer 6

Sinus pause/arrest (2 seconds to minutes)
time for dissipation of hyperpolarizing (overdrive) current

allows escape beats/rhythm - subsidiary conduction taking over

can be life threatening

Question 7

Answer 7

Overdrive suppression is a consequence of heart rate being greater than subsidiary cells inherent firing rate

Question 8

Answer 8

The mechanism for overdrive suppression is hyperpolarization due to increased Na⁺ efflux

Question 9

What enzyme is associated with overdrive suppression?

Answer 9

Na/K ATPase

Question 10

What impact does the heterogenous tissue of the SA node have on conduction velocity?

Answer 10

When the SA node starts the electrical signal this is initially slow conduction, by the end however the velocity of conduction increases

Question 11

What is the physiologycal response to sympathetic stimulation of the SA node?

AV node?

Answer 11

• Positive Chronotropic Effect (Nori, Epi, B₁ receptor agonist)
  
  • SA Node
    
    • increased rate of rise of DD (Phase 4)
      
      • I_f increased
      • rapid decrease in gK
    • increase gCa
      
      • reach threshold sooner
    • no change in MDP
    • shorter duration AP
    • as you can see in the graph, the slope of the slow diastolic depolarization changes so we reach threshold faster & that is what gives you a faster heart rate
  • AV node
    
    • accelerated conduction due to increased gCa
• In image, top = SA node; bottom = AV node

Question 12

What cells make up the SA node?

Describe the electrical coupling of the SA node. How well does it connect with surrounding cells?

Describe the quantities of desmosomes, gap junctions, and mitochondria in this region.

Describe the arrangement of sarcomere/myofibrils. How does this effect the force of contraction?

Answer 12

SA node made up of P cells

P cell - empty/pale cell, few desmosomes, few gap junctions

poor electrical coupling - surrounded by cells with high electrical coupling that can invade and mess things up - isolation is important

few mitochondria

few sarcomere/myofibrils in irregular arrangement (not productive)

multidirectional force is weak if any

Question 13

Describe how surrounding cells could interfere with rhythmicity of SA node?

Answer 13

P - pale cell

W - working cell
(membrane potential is -90)

T - transitional cell

Should working cells invade the SA node (pale cells) this will interfere with action potentials and rhythmicity

Important that SA node and pale cells are isolated

(membrane potention is -50)

Question 14

While moving from deep to superficial regions of the heart what characteristic of the heart changes action potentials allowing them to escape the isolation of the SA node?

Answer 14

Heterogeneity of the SA node allows for increasing amplitude of action potentials allowing the electrical signal to escape the confines of the SA node which is surrounding by muscle

Question 15

What membrane voltage-gated, time-dependent currents lend to action potentials of pacemaker cells?

What electrogenic transporters carry current and contribute to action potentials of pacemaker cells?

Describe the location of sodium channels and I_K1 channels in the SA Node.

What’s going on with Purkinje fibers and the AV node in regards to sodium channels and I_K1 channels?

Answer 15

_Membrane voltage-gated, time-dependent currents_
Sodium current (I<sub>Na</sub>)
Funny current (I<sub>f</sub>)
Calcium current (I<sub>Ca</sub>)
Potassium current (I<sub>K</sub>)

Electrogenic transporters
Na⁺/Ca²⁺ Exchanger (I_NCX)
Na⁺/K⁺ ATPase

SA Node
heterogeneous, site specific sodium channels
sodium channels not in the center, but present in periphery
No I_k1 channels - which causes the unstable baseline

Purkinje fibers have sodium channels

AV Node does not have I_K1 channels

Question 16

What two “clocks” contribute to the rhythm and timing of action potentials formed by the center of the SA node?

Answer 16

Membrane clock
ensemble behavior of ion channels
time-dependent behavior

Calcium clock
spontaneous release of Ca from SR
local calcium release (LCR)

Question 17

What membrane voltage gated ion channels contribute to pacemaker ticking functions? What activates these channels?

What SR function contributes to the ticking function of pacemakers?

Answer 17

Membrane ion channels
Funny channels - activated by cAMP and hypopolarization
Calcium channels - depolarization
Ca/K channel exchange channels - local calcium release

SR related
spontaneous local calcium release

Question 18

What induces initial calcium influx through the calcium channels located on the membrane of pacemaker cells?

What is the initial influx of calcium called?

What does this induce?

Answer 18

Initial calcium influx through calcium channels is activated through depolarization

this initial influx is called the spark in pacemaker cells

this induces calcium induced calcium release

results in action potential and depolarization

Question 19

What causes the activation of the following channels?

funny channels
calcium/potassium exchange channels
transient calcium channels
L type calcium channels

What causes repolarization of the SA nodal action potentials? What causes the difference between repolarization of muscle cells and the SAN cells?

What causes the slow unstable diastolic depolarization?

Answer 19

Funny channels opened around -55, during hyperpolarization - results in influx of sodium which prevents further hyperpolarization

Sodium/Calcium Exchange activated by calcium clock - results in further depolarization with influx of 3 sodium and efflux of 1 calcium

Transient Calcium channels opens during diastolic depolarization

L type calcium channels open when threshold is reached to cause slow depolarization

Repolarization of SA node
Potassium channels, specifically I_to1, open allowing rapid efflux of potassium leading to diving repolarization without a plateau phase that is present in muscle cells (due to high to1)

Slow unstable diastolic depolarization
caused by funny channels influx sodium - stopping hyperpolarization
caused by sodium/calcium exchange pumping out calcium and bringing in 3 sodium

Question 20

What is the role of the Na/K ATPase during the action potential of SA node?

What goes in and out?

What does this lead to?

Is this pump responsible for phase 3 repolarization?

Answer 20

Na-K ATPase

maintains electrochemical gradient (3 Na out:2 K in)

net outward current leads to hyperpolarization

not responsible for phase 3

In pacemaker tissue can contribute to maximum diastolic potential - thus can influence pacemaking

Question 21

How does the action potential change as it potentiates from the center of the SA node to the periphery?

Summarize the roles of the center cells and periphery cells of the SA node. Where is conduction fastest?

Answer 21

The center action potentials are low in amplitude and rely on calcium channels resulting in slow depolarization.

This expands breaking through the higher resting membrane potential of the outer cells which rely on sodium channels, and have action potentials which appear more similar to myocytes.

In short:
SAN center cells - ensure electrical isolation and automaticity, slow conduction
periphery cells - allow rapid exit of the AP, faster conduction, (more negative maximal diastolic potential?)

Question 22

Answer 22

Unstable resting membrane potential

Question 23

Answer 23

Relative absence or presence of Na+ channels

Question 24

What do funny channels prevent?

Answer 24

Hyperpolarization

Question 25

Answer 25

K currents overwhelm Ca currents

Question 26

Answer 26

Opening of calcium channels

Question 27

After the AP leaves the SA node where does it go? Specifically? What is the conduction velocity? What does the AP look like?

Answer 27

Goes to atrial muscle, specifically the intermodal pathways and inter atrial tract (Bachman's bundle) to left atrium Conduction velocity 1m/sec

Question 28

When the AP leaves the atrial muscle where does it go? What does this AP look like? Conduction velocity? What characteristics does this node have that are similar to the SA node? What cell types will you find here?

Answer 28

_Similar to SA node in_ poor electrical coupling low conduction velocity long "natural" refractory period automaticity ``` _Cell types_ P cells transition cells (slow) Purkinje cells (fast) ```

Question 29

What are the three regions of the AV node and what cell types are found there? What characteristics does this lead to? How does the refractory period play with AP gone rogue?

Answer 29

``` _AN region (transitional region)_ no P cells no automaticity - an AP will not come from here, will be from lower down ``` _N region_ P and T cells slow conduction with long refractory period long refractory period stops rogue AP most of the time which is good _NH region_ Purkinje and T cells

Question 30

Where does the AP travel after the AV node? What is the conduction velocity? Where does the AP go from there? Conduction velocity?

Answer 30

Bundle of His Conduction velocity 1-2 m/sec Right and Left Bundle Branch Conduction velocity 2 m/sec

Question 31

Where does the AP go from the left and right bundle branches? What cell types do you find here?

Answer 31

_Purkinje fibers_ Pale cells (like SA node) but more gap junctions glycogen rich few more myofibrils - slightly more organized

Question 32

Describe the speed of conduction and intrinsic rhythm of purkinje cells. What characteristics of the purkinje cells lead to the conduction speed? What channels are the most important to prevent hyperpolarization? The action potentials of purkinje cells are appear similar to what other type of cell? What channels contribute to the stable baseline? What function of the purkinje cells is due to the conduction speed?

Answer 32

_Purkinje cells_ Fast conduction (2-4m/sec), slowest intrinsic rhythm **More gap junctions and Na channels** - fast conduction **funny channels** very important - prevent hyperpolarization at lower membrane potential AP like working cells - stable phase 4 due to I_K1 rapid activation of entire endocardial surface of ventricles (due to fast conduction) **long refractory periods** - good to stop irritation sending more APs

Question 33

Where does the action potential go after Purkinje fibers? What does this action potential look like? What path does this take? What is the conduction velocity?

Answer 33

Action potential goes from purkinje fibers to the ventricular muscle. Path goes from endocardial to epicardial Conduction velocity 0.3-1 m/sec (slow intrinsic rhythm - 25/bpm)

Question 34

Answer 34

Purkinje cells have rapid conduction because They have large cells phase 0 is carried by sodium channels many gap junctions stable baseline

Question 35

What advantage is conferred by the relative long refractory period of Purkinje cells?

Answer 35

Block premature impulses that get through the AV node

Question 36

What is the normal range of human heart rate? What factors influence extrinsic modulation?

Answer 36

* Heart rate 30-240 b/min 1. rate or rise of diastolic depolarization; Phase 4 2. Changing the Maximum Diastolic Potential (MDP) * funny channels prevent hyperpolarization, so they determine the maxiumu diastolic potential; * Also the role of Na/K ATPase in suppression & can play a role in determining MDP 3. Phosphorylation state of the cell (impacted by autonomic nervous system) * L-type Ca²⁺, and various K⁺ channel activation * funny channels - cAMP

Question 37

Describe the molecular response of the SA node to sympathetic stimulation

Answer 37

* When agonist of B₁ binds, see stimulation of adenylate cyclase * increased concentration cAMP * directly binds to I_f & accelerate function * increase in PKA so phosphorylation state of hte cll increases * I_Ca,L - increased rates Ca entering cell * faster depolarizaion * affecting time it takes to get to threshold * I_K - increased rates of K exiting the cell * faster repolarizaion * changes duration of refractory period & thus heart rate * RYR - Can can move out of SR faster * Phospholambam (inhibits the inhibitor -- cannot inhibit SERCA) - faster Calcium uptake into the SR

Question 38

Describe the molecular response of th SA node to parasympatheti stimulation

Answer 38

* Ach binding to M₂ receptor * g_By : binds with I_K,Ach * leads to potassium leaving the cell --\> hyperpolarizaion & plays an important role in slowing things down * g_ai : inhibits AC = less cAMP = less PKA & I_f slower * cell gets dephosphorylated & slow everythign down * Lengthen refractory period b/c I_K dephosphorylated * I_f not stimulated by cAMP = slow diastolic depolarization rate

Question 39

What is the physiological respons of SA node stimulation by the parasympathetic nervous system? AV node?

Answer 39

* Negative Chronotropic Effect (Acetylcholine; M₂ receptors) * Reduction of heart rate * SA Node * decreased rate of rise of DD * decreased I_f and I_Ca (Phase 4) * MDP more negative * increased gK durign Phase 3 & 4 * you can see the slowing of the diatolic depolarization by the decreae in slope * AV Node * slowed conduction due to decreased gCa

Question 40

What is the bowditch effect?

Answer 40

The link between chronotropic & ionotripc effects increased contractility associated with increased rate * When you have changes in you local calcium currents * **LCR - Ca²⁺ release for timing (sparks)** - rate * Na⁺ "accumulates" with increased rate * Na⁺-Ca²⁺ exchanges favors Na⁺ efflux, [Ca²⁺]_i influx * **Ca²⁺- induced Ca²⁺ release - SR release via RYR** - in nodal cells = timing function; ventricular cells = force * increased [Ca²⁺]_i * increase inotropic state - increased contractility * When heart is beating faster, you will typically see an increase in contractility due to the impacton the rate of Ca influx; the reverse is true when the hear is beating slower * **Synchronization of RYR activation spark and trigger Ca²⁺**

Question 41

Answer 41

[B₁] b. phosphorylating L-type Ca²⁺ channels

Question 42

Answer 42

[B₁] b. increasing the rate of diastolic depolarization

Question 43

Answer 43

[M₂] b. opening I_k,Ach channels c. decreasing the rate of diastolic depolarization (cAMP affects funny current)