Cardiovascular Electrophysiology

Question 1

What factors regulate mean arterial pressure (MAP)?

Answer 1

Many factors can regulate the mean arterial pressure.

Question 2

What are the two cell types in the myocardium?

Answer 2

Contractile cells & autorhythmic/pacemaker cells

Question 3

What are the main features of contractile myocardial cells?

Answer 3

• the predominant cardiac cell type (cardiac myocytes)
• can contract in response to an action potential
• can also propagate the action potential

Question 4

What are the main features of autorhythmic/pacemaker cells?

Answer 4

• specialized muscle cells that are not involved in the generation of force (do NOT contract)
• will both initiate & propagate action potentials
• includes cells of the sinoatrial node, atrioventricular nodes, Bundle of His, & Purkinje fibers

Question 5

What are the four primary characteristics of cardiac cells?

Answer 5

1. Automaticity
2. Excitability
3. Conductivity
4. Contractility

Question 6

True or false:

All cardiac cells have the membrane potential & action potential curve.

Answer 6

False.

Different cardiac cell types (contractile vs autorhythmic) will have different potentials & different action potential curves

Question 7

Which of the two types of cardiac cells only exhibit 3 of the 4 primary characteristics of cardiac cells?

Answer 7

Autorhythmic/pacemaker cells.

These cells exhibit only 3 of the 4 primary characteristics of cardiac cells, as they do not have contractility (they do NOT contract in response to an action potential)

Question 8

Which cell type action potential is pictured here?

Answer 8

Contractile cell action potential; specifically ventricle cells

Question 9

Which cell type action potential is pictured here?

Answer 9

Contractile cell action potential; specifically atrial cells

Question 10

Which cell type action potential is pictured here?

Answer 10

Autorhythmic cell action potential; specifically sinoatrial (SA) node (aka pacemaker)

Question 11

What are the phases of the fast cardiac action potential? What ion movement is responsible for each phase?

Answer 11

0. Upstroke
   - Sodium channels open and sodium rushes into the cell until the cell membrane reaches a positive membrane potential
1. Early repolarization
2. Plateau
   - Calcium & Potassium channels open, allowing calcium to flow into the cell slowly, and potassium on the other hand to begin rushing out of the cell
3. Late repolarization
   - Calcium influx tapers off & potassium continues to rush out of the cell
4. Baseline
   - cardiac cell membrane returns to its baseline/resting state at -85mV

Question 12

What is the baseline membrane potential for a cardiac cell?

Answer 12

-80 to -90 mV (close toequilibrium for potassium)

Question 13

What is phase 4 of the fast cardiac action potential?

Answer 13

At phase 4 the myocyte is at rest.

• -80 to -90 mV
• ions moving across membrane to maintain electrical & concentration gradients
  -predominant potassium conductance sets resting membrane potential
• at rest there isa slight outward diffusion of potassium

Question 14

What is the threshold for a cardiac cell to have an action potential?

Answer 14

-50 mV

At -50mV, sodium ion channels open rapidly and allow rapid influx of sodium into the cell, causing depolarization.

Question 15

What is phase 0 of the fast cardiac action potential?

Answer 15

Fast activation of sodium channels causes the upstroke.

-channels open and membrane depolarizes rapidly (increase by 70mV in 1-2 ms)

Question 16

What is the “h gate”?

Answer 16

The gate on the sodium channel protein that closes slowly and inactivates the channel during the absolute refractory period

Question 17

What is the “m” gate?

Answer 17

The activation gate on the sodium ion channel. It is closed at rest (-70mV) but is capable of being opened to allow depolarization to occur. This gate is in play when the cell is at rest and during the relative refractor period.

Question 18

At what voltage are the potassium channels activated/opened?

Answer 18

At +35 mV the potassium channels will open and allow potassium to flow out of the until the cell hyperpolarizes at -90 mV. At -90 mV the cardiac cell is at it’s resting membrane potential & the potassium channels will close back up.

Question 19

What is happening during phase 1 of the fast cardiac action potential?

Answer 19

Early repolarization occurs due to a Transient Outward current (Ito).

• Sodium channels are closed
  -Potassium and Calcium channels open (K+ flows out, Ca2+ flows in)
• Ito1 = voltage-gated, calcium INDEPENDENT, potassium current OUT of the cell (these gates are rapidly activated and inactivated)
• Ito2 = calcium activated (DEPENDENT) chloride current (not well understood!)

Question 20

What is happening during phase 2 of the fast cardiac action potential?

Answer 20

Phase 2 is the plateau phase.

• Calcium continues to flow inward (inward conductance)
• Potassium continues to flow outward (outward conductance)
  -Initially the influx (inward flow) of positive charged carried in by the Ca2+ is balanced by the efflux (outward flow) of positive charge carried by the potassium. This is what causes the plateau on the action potential graph.

Question 21

What is happening during phase 3 of the fast cardiac action potential?

Answer 21

Phase 3 is Final repolarization.

• begins at the end of phase 2, when the outward flow of potassium begins to exceed the inward flow of calcium, causing a break in the plateau as the cell membrane repolarizes (becomes more negative)
• The calcium channels close and the calcium current is inactivated.
• Replarization is due to the potassium currents that dominate during this phase (Ik & Ik1)

Question 22

Why does the action potential graph for autorhythmic cells look so different from that of cardiac cells?

Answer 22

The autorhythmic cells fire or depolarize spontaneously & fire action potentials at a regular rate without direct signal from nerves (though their automaticity is influenced by both the parasympathetic & sympathetic nervous systems).

Autorhythmic cell action potentials only have 3 phases whereas cardiac cell action potentials have 5 (0-4).

The Autorhythmic cells start in phase 4, go to phase 0, then to phase 3.

Question 23

What are the key features of autorhythmic cell action potentials?

Answer 23

Autorhythmic cells of the heart include the cells of the SA node, AV node, bundle of His, & Purkinje fibers. These cells:

-do not contract; contain no contractile machinery & are only 1/3 size of the surrounding contractile myocytes/cardiac cells.

• have slow action potentials

-depolarize spontaneously, & fire action potentials at a regular rate

• rhythmiticity is modulated by channels active at or near threshold
• the native/main pacemaker current driving depolarization is the “funny” current (If) (calcium currents)(though not the only current contributing to change in membrane potential)
• no phase 1 & phase 2 cannot truly be distinguished from phase 3 (early repolarization & plateau phases); only contains phases 4, 0, & 3.
• phase 0 is less steep than seen in cardiac cell action potentials
• Unstable phase 4; shows an upward slope instead of being flat
• does NOT contain any fast sodium channels; depolarization is achieved by Ca2+ currents

-is non selective for Na+ & K+; is cAMP (& calcium) dependent.

-HCN (hyperpolarization channel believed to be molecular identity of the pacemaker current

Question 24

What are the key differences between the action potential profile of autorhythmic cells vs that of cardiac cells?

Answer 24

Most notably:

-the resting membrane potential is more depolarized than that observed in atria and ventricle. Autorhythmic cells have a resting membrane potential closer to -70 mV while cardiac cells are between -80 mV & -90mV.

-Phase 0 is less steep and can be accounted for by Ca2+ currents.

-Fast Na+ currents are absent.

-The plateau phase (phase 2) is ill defined and there is no repolarization notch (phase 1) observed at all.

• Finally, there is a less obvious division between phase 2 and phase 3.

Question 25

What occurs during the phases of an autorhythmic cell depolarization?

Answer 25

1. Phase 4 - cell is at resting membrane potential of ~70mV, but is unstable and slowly depolarizes under the influence of the HCN (hyperpolarization-activated cyclic nucleotide) gated channels which facilitates the “funny” current (If) to flow inward until reaching the cell reaches the -50mV threshold. 2. Phase 0 - Once the cell has reaches threshold, low-voltage activated T-type calcium channels are activated and allowing calcium influx which contributes to the early depolarization of phase 0 & the action potential upstroke. 3. Phase 0 continues - L-type calcium channels then open as well, allowing even more calcium influx into the cell, further enhancing depolarization. 3. Phase 3 - Once the action potential has reached its peak positive voltage, the potassium channels open & the Ik currents are activated, allowing potassium to flow out of the cell causing repolarization, and the whole cascade repeats with the If current causing slow depolarization toward threshold. As If (funny current) becomes more active again, the Ik (potassium current) declines.

Question 26

True or False: How one cardiac cell influences another electrically is dependent on the voltage difference between the cells and the resistance of the gap junctions that form connections between them.

Answer 26

True

Question 27

What are gap junctions? Where are they found? In the heart tissue?

Answer 27

Gap junctions are small pores/closed channels that traverse the extracellular space between cells, connecting them along with the desmosomes which provide the stronger mechanical attachment between the myocytes. They allow for movement of both ions and signaling molecules; are responsible for electrical coupling (propagation of the action potential as local currents flow between adjacent cells thereby depolarizing the neighboring cell); enables cardiac tissue to behave as a functional synctium Gap junctions (as well as desmosomes) are found in the intercalated discs, the region where two myocytes join end to end.

Question 28

What is the sequence of electrical signal conduction through the heart?

Answer 28

SA Node > Atria> AV Node > AV Bundle/Bundle of His > Bundle branches > Purkinje fibers > Ventricles

Question 29

True or False: The atria and ventricles contract at the same time.

Answer 29

False. Based on the sequence of signal conduction through the heart, the atria will contract before the ventricles.

Question 30

What node is termed the pacemaker & Why? What rate does the pacemaker set the heart at?

Answer 30

The sinoatrial (SA) node is also called the pacemaker because the SA node is the fastest and the heart rate is set by the fastest node. The SA node sets the resting heart rate between 60-100 “beats” (action potentials) per minute.

Question 31

At what rate does the atrioventricular (AV) node fire?

Answer 31

40-60 “beats” or AP (action potentials) per minute

Question 32

At what rate do the Purkinje fibers fire?

Answer 32

25-40 “beats” or AP (action potentials) per minute

Question 33

What two important functions does the conduction system of the heart serve?

Answer 33

1. Relays the wave of depolarization from the atria to the ventricles (only through the AV node because of connective tissue) 2. Delay spread of excitation (AVN cells conduct slowly)

Question 34

AVN cells conduct electric signals fast or slow?

Answer 34

Slow. They have the slowest conduction velocity.

Question 35

Bundle of His & Purkinje fiber cells conduct electric signals fast or slow?

Answer 35

Fast. They conduct electric signals the fastest.

Question 36

What are factors that can influence or modulate the electrical activity of the heart?

Answer 36

- Electrolytes - blood pH - mechanical disturbances (stretch can increase HR) - Hormones/autocrine/paracrine substances - Drugs -Autonomic Nervous System

Question 37

What is the bodies principal controller of heart rate and how does it affect the HR?

Answer 37

The Autonomic nervous system is the principal controller of the heart rate. The sympathetic nervous system (SNS) increases heart rate & also increases contractility of the myocytes. The parasympathetic nervous system (PNS) decreases heart rate.

Question 38

What is the normal adult heart rate at rest?

Answer 38

~70 bpm

Question 39

Review: Which cranial nerves have parasympathetic outflow?

Answer 39

Cranial nerves 3, 7, 9, & 10 (vagus)

Question 40

The heart beat is controlled by both the SNA & the PNS divisions of the ANS, thought the PNS tone usually predominates. What would happen if both divisions of the ANS are blocked? Would the heart still beat?

Answer 40

Yes the heart can still beat. With both divisions of the ANS blocked, the heart will have a prevailing rate known as the “intrinsic heart rate”, which is typically set by the SA node.

Question 41

What messenger cascade system does the autonomic nervous system use to regulate the electrical activity of the heart?

Answer 41

G proteins. Acetylcholine and catecholamines modulate pacemaker activity, conduction velocity, and contractility. Acetylcholine uses G protein coupled receptors to convert ATP to cyclic AMP (cAMP) in the adenylate cyclase coupled g protein receptor pathway (GsA)

Question 42

How does the parasympathetic nervous system affect the autorhythmic cell action potential?

Answer 42

PNS will release Acetylcholine via the Vagus nerves, which will cause the intrinsic pacemaker activity of the SA node to SLOW DOWN, via 3 major mechanisms: 1. First, via Gi (inhibitory G-protein A): Gi inhibits adenylyl cyclase causing cAMP levels to decreased, which leads to a decrease in the activity of If (funny current) ,the pacemaker current, which reduces the steepness of phase 4 of the pacemaker AP. 2. Second, a decrease in cAMP also leads to a decrease in L-type Ca channel activity which makes the threshold of activation more positive & the net effect is that it takes longer to reach threshold. 3. Third, Ach acts via a mechanism not involving cAMP to activate IKACH channels (potassium acetylcholine channels). The result is an increase in K conductance and the cell membrane potential is driven toward EK (equilibrium for potassium, which is closer to resting membrane potential) and hence becomes more negative. **Ach also has similar effects on the AV node; slows conduction velocity by inhibiting the ICa (calcium flow into the cell). The effect is to make the threshold potential more positive thus making it more difficult for one cell to depolarize its neighbors.

Question 43

How does the sympathetic nervous system affect the autorhythmic cell action potential?

Answer 43

Catecholamines, either norepinephrine or epinephrine, act through B2 receptors and produce an increase in heart rate through 2 main mechanisms: 1. First, catecholamines via Gs (stimulatory G-protein pathway) lead to the activation of adenylyl cyclase, thereby increasing the levels of cAMP. Increased cAMP enhances If (funny current) activity which leads to an increase in the steepness of phase 4 depolarization. 2. Second, cAMP activates PKA which leads to phosphorylation (activation) of Ca channels (to allow calcium to flow into the cell). This makes the threshold more negative therefore the cells fire more readily. In addition to the effects on rate of firing, the increase in Ca levels in the cell are also involved in increased contractility.