Molecular control of Pacemaking Flashcards
AP of the PMC
- Depolarise on hyper polarisation due to HCN (If channels)
- Upstroke is slower as no rapid Na channels (Nav1.5)
- Repolarisation is more constant (not like VCM’s plateau)
Origin of the nodes
- Believed to be remnants of primary myocardium
- Possibly derived from 1st HF
- Repression of contractile phenotype differentiation
Repression of Chamber Myocardium differentiation
- Tbx18, Tbx3
- Isl1
- Shox2
Induction of Chamber Myocardium
- Tbx5, Tbx20
- Nkx2.5
- Nav1.5 expression for rapid
depolarisation - Pitx2 (suppresses PMP)
Development of the SAN
- Where
- Molecular queues in morphology
- On the right, between IVC and SVC
Head
- Compact area containing centre (Tbx18)
Tail
- More fragmented, more fibroblasts (Nkx2.5)
The 2nd HF in PMC origin
- Posterior and anterior compartments
- Signalling with BMPs, FGFs, nodal, TBx5, Nkx2.5, Isl1
- Isl1 expression maintain most primitive stage of differentiation
Electrical mapping of PM centre in development
- In linear HT, comes from left side
- Left side centre maintained after looping
- Cells recruited to IFT, migrate to AV junction
- PM program seals fate of cells once in the right position
PMCs and the 3rd HF
- PMCs originate on the right side, far from the 1st HF
- Unique, posterior position
- Wnt8 specifies 3rd HF
(Crescent inhibits this)
The PMP
- Initiators
- Promotor (expansion, specification)
- Suppression
- Shox2 and Isl1
- Tbx18
- Pitx2
PMC Channel and GJ expression
- HCN4, Hcn1 and Hcn2
- Cav1.3 and Cav3.1
- Cx30.2 (slow conducting Cx)
Working CM expression
- Nppa, Nppb (BNP and ANP)
- Cx43, Cx40 (fast Cx)
- Scn5 (Nav1.5)
Non-PMCs of node region
- Lots more collagen and fibroblasts than myocytes
- Transitional cells with some properties of PMC and WMC (Nav1.5)
- Conduct AP to crista terminalis (first WMC to depolarise)
PMCs of the node
- Myocytes are small and thin
- Elongated spindle, spindle or spider shape
- Poor electrical coupling between cells
(few GJ, slow Cx)
Elongated Spindle and Spider PMCs
Elongated spindle
- Possibly link the SAN to surrounding atrial myocardium
Spider
- Possibly where the AP is first produced
HCN4, Nav1.5 and Cx43 in the SAN and WCMs
- HCN4 mostly in centre, some in periphery, none in WCMs
- Nav1.5 and Cx43 in WCMs, some in periphery but none in centre of SAN
SAN vs atrial ion channels and pumps
Atria
- Nav1.5
- RyR (relatively more)
SAN
- HCN4
Currents of SAN AP
Phase 4:
- I(f) initially
- then I(Ca-t)
- then I(Ca-l)
Phase 0:
I(Ca-l)
Phase 3:
- I(K)
Currents of VCM AP
Phase 4:
- I(K)
Phase 0:
- I(Na)
- I(Ca-t)
- I(Ca-l)
Phase 1:
- I(K-to)
- I(Ca-l)
Phase 2:
- I(Ca-l)
Phase 3:
- IK1
SAN vs VCM AP
- Amplitude
- Depolarisation
- GJs
Amplitude:
- Small vs Large
If:
- Present vs Absent
Nav1.5
- Absent vs Present
GJs
- Sparse/slow vs Abundant/fast
Channels of the PM potential
- HCN4
- RyR
- T-type Ca
- (Nav1.5)
- Blocking any of these slows heart rate
- Redundancy, loss of no one current can silence the PM potential
Interconnected Clocks
- Ion flux across the cell membrane
- Ca storage and release from SR
- ‘clocked’ release of SR Ca make NCX efflux Ca
- Na influx causes depolarisation
- depolarisation causes Ca influx
- Ca content of SR influences NCX behaviour by leaking
Sick Sinus Syndrom
- Who gets it
- What is it
- How common?
- What is cause?
- Disease of the elderly
- Bradyarrhythmia due to dysfunction of SAN
- Reason for 50% of implanted PMs
- Mutations in HCN4 or SCN5a*
- Nav1.5 believed to be important in conducting AP from SAN to WCMs
The Biological PM
- Cell therapy (SCs)
- Hybrid therapy (SCs + Hcn2)
- Gene therapy (Tbx18 viral transduction)*
- Could reduce need for implanted devices
- most promising
