Mechanisms Of Heart Rate Regulation Flashcards
Why are we interested in modulating heart rate (HR)? (2)
HR is a predictor of CVD morbidity/mortality in acute and chronic disease
Resting HR above 70 beat/min considered to increased risk
Why is increased resting heart rate considered a risk? (6)
-increased HR linked to atherosclerosis/coronary artery plaque disruption
-Determinant of myocardial O2 consumption
-Determinants of coronary circulation perfusion time
=
-decreased HR leads to a increased O2 demands of heart
-increased Coronary perfusion
-decreased HR is a target for treating post-MI, angina, heart failure etc.
Use of B1 blockers, Ca2+ channel blockers
Where is HR initiated and regulated?
Sino-atrial node (SAN)
What is the SAN? (3)
-Primary area generating pacemaker potentials in the heart
-Provides the initial electrical stimulus for myogenic activity of the heart
-Direct relationship b/w pacemaker frequency and heart rate (HR)
Where is the SAN?
Textbook answer: A small nodule of specialised cells at the junction of the SVC with
the RA
Is this correct?
The ‘real’ SAN
image (dorsal view)
Red: SAN node
Blue: peripheral SAN node
Area of SAN is a much more extensive structure than thought:
Measuring electrical activity : area affected by vagal stimulation
Staining : neurofilament (SAN + atrial myocytes), Cx43 (atrial myocytes),
ANP (atrial myocytes)
– area of no Cx43/ANP but neurofilament staining = SAN
Properties of SAN (6)
-SAN cells: electrical generating not contractile/conduction
-Express HCN4 proteins – make up If channels (HCN4 proteins are not present in other areas of the heart)
-Central SAN areas are surrounded by fibrosis/connective tissue
-Do not express connexins (e.g., Cx43, like atrial myocytes),
-Poor gap junction structure
-SAN is electrically isolated from rest of heart
Why is SAN electrically isolated from rest of heart (2)
-Pacemaker potentials leave SAN and spread into atria through specific pathways – currently unclear
-SAN is not influenced by atrial electrical activity
= This could ‘switch-off’ SAN
Relationship of pacemaker potentials, other cardiac
action potentials - pathway (6)
image
1) SAN = contraction (diastolic depolarisation)
2) spread to Atrial muscle (both left +right) = electrical activity, coupled to = contraction
3) electrical activity spread to AVN = slows down A.P. = ejection + filling of ventricles = conduction to Bundle branches
4) Bundle of HIs, Bundle Branches
5) Purkinje Fibres
6) Ventricular tissues
ECG and Electrical activity
Electrical PATHWAY CREATES ECG (measuring this electrical pathway) = changes e.g. rate/rhythm conduction pathway
What distinguishes these action potentials from each other? Hence, causing the pacemaker potential? (3)
stable vs unstable resting membrane potentials
The pacemaker potential causes a diastolic depolarisation during the resting period of the heart
SAN begins to depolarise = creating another A.P = initiate another heartbeat
Ionic basis of pacemaker potential – Recap
image
Activation of If initiates diastolic depolarisation= forms ionic basis for initiating pacemaker activity, in absence of external stimuli
But not so simple…….
This voltage clock interacts with a ‘Ca clock’
New Understanding
image
Pacemaker potentials are a complex interaction b/w Voltage and Ca2+ clocks
What is the Voltage Clock? (5)
image
If channels: Hyperpolarisation-activated cyclic nucleotide (HCN) channels formed by HCN4 proteins; activated at <-45 mV
Linear phase
VGCCs: 1)L-type VDCC – activated -40 mV, long lasting activation;
2) T-type VDCC – activated -70 mV, transient activation
INaCa: NaCa exchanger (NCX) – what is this role? Linked to Ca2+ Clock
Exponential phase
What is the Ca2+ Clock? (3)
image
By removing the rise of [Ca2+]i = activate NCX = influx of Na+ = depolarisation
What comes first – Voltage or Ca2+ Clock? (3)
-LCRs: Localised Ca2+ releases
-Not influenced by depolarisation
-Occur during late diastolic depolarisation
Does Ca2+ clock therefore drive
voltage clock?
What determines speed of Ca2+ Clock? (3)
IT’S TICKS!!!!!!
-Tick speed determine pacemaker potential frequency and heart rate
-Speed of release/depletion of SR Ca2+ stores – RyR activity
-Speed of SR Ca2+ recycling – SR SERCA activity
What are it’s ticks influenced by? (8)
Constitutive PKA activity:
-SAN express constitutively active adenylate cyclase isoforms
-Produces cAMP-mediated PKA phosphorylation of RyR
-Increases opening of RyR and greater release of Ca2+ from SR
Pacemaker potential frequency:
-More Ca2+ influx through T/L-type Ca2+ channels,
-Greater uptake of Ca2+ into stores
-More to be released
Summary of evidence for Ca2+ Clock drives voltage Clock (6)
Block of Ca2+ cycling:
-Buffering [Ca2+]i to low levels slows/stops
pacemaker potential activity
Block RyR:
then decreased LCRs + pacemaker potential frequency
Block L-type Ca2+ channels or prevent depolarisation:
then decreased Ca2+ entry, decreased SR refilling, block LCRs, + pacemaker potential
failure
LCR-evoked INCX triggers pacemaker potentials
graph
Ryanodine - RyR inhibitor
Li+ -NCX inhibitor
INCX -involved in exponential
increase in diastolic depolarisation
Importance – Voltage (If channels) or Ca Clock?
images explained
Autonomic control of heart rate
Through If channels or Ca2+ clock? (5)
image
Both Sym and Parasym NS alter
rate of diastolic depolarisation NOT firing threshold!!
Sym: B1 - Gs - AC - increased cAMP – increased If – faster rate of diastolic depolarisation
Parasym: M2 - Gi - decreased AC - decreased cAMP – decreased If – slower rate of diastolic depolarisation
Remember :
1) increased cAMP leads to increased PKA activity, and PKA-phosphorylation of RyR induces more LCRs, evoking increased INCX
2)Parasym will also reduce Ca2+ clock
If channels mediated by HCN proteins channels are clinical targets (7)
- If channels – ‘funny’ currents
-Activated by membrane hyperpolarisation
-Unique - normally voltage-gated channels activated by depolarisation
-HCN are the molecular correlates of If channels
-Four distinct members (HCN1-4)
-Expressed HCN cDNA in cell lines – you get If channel currents
-Increased activity by cAMP
image
Expression of HCN proteins in the heart
table
A HCN modulator : Ivabradine (6)
images
- (S16257, procoralan) - only If channel blocker clinically available
-Blocks all HCN isoforms
-Little effect on other ion channels (Na+, K+, Ca2+)
-blocks If currents + prolongs pacemaker potentials
-Oral, 50% bioavailability
- decreased heart rate by 10-20 beats/min in healthy individuals – good safety profile
Clinical evidence for Ivabradine
bare results
Clinical evidence for Ivabradine- SIGNIFY trial
Study assessInG the morbidity-mortality beNefits of the If inhibitor
Ivabradine in patients with coronarY artery disease
extra
NICE Ivabradine guidelines
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