Molecular control of pacemaking and conduction

Question 1

Main function of AVN

Answer 1

Retard impulse propagation so atria contract before ventricles

Question 2

Difference in membrane potential of pacemaker cells/AV node cells to myocyte cells

Answer 2

no resting membrane potentials - The moment that there is hyperpolarization after the end of the AP reached, the next AP will be generated rapidly by the opening of specific ion channels - HCN channels

Question 3

Why is AP slower to uprise is nodes

Answer 3

Absence/weak expression of Na⁺ channels in node cells

Question 4

Difference in plateau of atria vs ventricle

Answer 4

strongly present in ventricular myocyte but much less present in atria. Reflects that pumping work of ventricle has a longer time constant relative to the more stretch like capacity of the atria.

Question 5

Which cardiac tissue has greatest AP amplitude?

Answer 5

Purkinje fibre network

Question 6

Which type of cell does primitive heart AP represent?

Answer 6

Pacemaker

Question 7

Which genes cause conversion of myocytes to fast pump acting myocutes and expression of Na channels and proliferation

Answer 7

Tbx5 and Tbx20

Question 8

Which genes important for Nodal cells

Answer 8

• A number of transcription factors collectively supress expression of Nkx2.5 and other transcription factors to repress chamber myocardium differentiation
• Tbx3: supresses expression of chamber myocardium genes
• Tbx18: supresses expression of Connexin 43
Shox2: supresses expression of Nkx2.5

Question 9

Which genes important for atrial cells?

Answer 9

Nkx2.5 (and Tbx5)
• Both have a stimulatory role for chamber myocardium genes
• Suppresses expression of Tbx3 and HCN4 (ion channel specifically expressed in SAN, particularly active during the pacemaker potential)

Question 10

Which gene stops SAN developing in left atrium?

Answer 10

Pitx2 - blocks Nkx2.5

Question 11

Location of SAN

Answer 11

border between caval vein and the right atrium

Question 12

Who discovered SAN and when?

Answer 12

Arthur Keith and Martin Flack in 1906

Question 13

Histological appearance of SAN

Answer 13

Node is consisting mainly of connective tissue (which allows nodal cells to be electrically isolated from surrounding chamber myocardium)

Question 14

What is the crista terminalis

Answer 14

specific bundle of cardiomyocytes in the RA, which initially receive the electrical signal from the SAN

Question 15

Molecular characteristics of SAN

Answer 15

absence of Nav1.5 and Cx43 expression.
○ Na⁺ channel expressed in chamber myocardial cells - channel is absent in SAN
HCN4 is abundantly expressed in the SAN (channel activated upon hyperpolarization)

Question 16

Gradient of expression/transitional cells

Answer 16

Note: gradient of expression seen
There is a change from pure SAN to a mixed character in the transitional zone connecting the node with the chamber myocardium

Question 17

Amplitude difference between SAN and ventricular myocytes

Answer 17

SAN: small
V: large

Question 18

Upstroke velocity difference between SAN and ventricular myocytes

Answer 18

SAN: slow
V: fast

Question 19

Funny current difference between SAN and ventricular myocytes

Answer 19

SAN: present
V: absent

Question 20

Na channel difference between SAN and ventricular myocytes

Answer 20

SAN: absent
V: present

Question 21

Gap junction difference between SAN and ventricular myocytes

Answer 21

SAN: sparse and slow
V: abundant and fast

Question 22

Funny current channel in pacemaker cells

Answer 22

HCN4

Question 23

Connexin responsible for gap junctions

Answer 23

Cx43

Question 24

Clock mechanism

Answer 24

–> The oscillatory activity of the SAN is driven by two interlinked mechanisms: the Ca²⁺ clock and the membrane clock
RyR release of Ca²⁺ from the SR, leads to an ↑Ca²⁺ concentration in the cytoplasm
SR function is to restore Ca²⁺ levels using SERCA (taking Ca²⁺ from cytoplasm to back into the SR)
Uptake and release → Ca²⁺ oscillation SERCA plays an important role in pacemaking

Any Ca²⁺ present in the cytoplasm can modulate the ion channels in the membrane. In particular:
Ca/Na⁺ exchangers move Ca²⁺ out in exchange for Na⁺ in

High Ca²⁺ concentration in cytoplasm, leads to inward movement of Na⁺, and transport of Ca²⁺ outside Inward flowing Na⁺ is determined by the amount of Ca²⁺ released by the cytoplasm – the Na2 current produced is believed to be important with regards to cardiac pacemaking

Question 25

What does phospholamban control

Answer 25

SR uptake system

Comlexes with SERCA2 to inhibit its activity

Question 26

How to inactivate phospholamban

Answer 26

Phospholamban itself can be phosphorylated and inactivated by adrenergic stimulation – hence this can influence the amount of Ca²⁺ stored and released from the SR

Question 27

SSS genetic causes?

Answer 27

HCN4
SCN5A (in transitional cells not SAN - poor conduction between pacemaker and surrounding myocardium)
Ankryin and MYH6 mutations are also thought to be associated

Question 28

What is SSS?

Answer 28

• is a pacemaker disease
Affecting mostly elderly people
Prevalent cause for pacemaker implantation (50% of all pacemaker implantations in patients over 65 is due to SSS)

Question 29

Problems with physical pacemaker

Answer 29

–> Wire can move, may become fibrotic, there is a finite lifetime and device may need to be exchanged (particularly if implanted early in life)
Additionally, linkage to physical activity/motion of the pt is usually not well-read by the artificial pacemaker

Question 30

Biological pacemaker types

Answer 30

Gene based biological pacemakers

Cell-based biological pacemaker

Question 31

Which gene shown potential for overcoming AV block

Answer 31

Tbx18