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Cardio and Resp diseases > Mechanisms of heart rate regulation > Flashcards

Mechanisms of heart rate regulation Flashcards

1
Q

What can heart rate predict?

A

CVD mortality in acute and chronic disease

• resting HR above 70 beat/min considered to  risk if you have CVD

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2
Q

Why is heart rate a predictor of CVD mortality?

A
  • increased HR linked to atherosclerosis/coronary artery plaque disruption and thus may lead to thrombus and occlusion of coronary artery
  • HR is determinant of myocardial O2 consumption – high HR implies the heart is less efficient
  • Determinants of coronary circulation perfusion time – every time there is a systolic contraction, there’s a reduction in coronary circulation perfusion time, high HR means more time is systole/less time in diastole and there’s a reduction in coronary perfusion
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3
Q

Why is decreasing heart rate a target for CVD treatment?

A
  • decreased HR leads to a decrease in O2 demands of heart
  • increase in Blood flow to heart
  • decrease in HR is a target for treating post-MI, angina, heart failure etc.
  • Use of beta1 blockers, Ca2+ channel blockers
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4
Q

Where is HR initiated and regulated?

A

Sino- atrial node (SAN)
• Primary area generating pacemaker potentials in the heart
• Provides the initial electrical stimulus for myogenic activity of the heart
• Direct relationship between pacemaker frequency and heart rate (HR)

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5
Q

What is the area of SAN determined by?

A
  • Measuring electrical activity: area affected by vagal stimulation – vagus nerve innervates the SAN
  • Staining: can stain neurofilament (SAN + atrial myocytes), Cx43 aka connexin 43 (atrial myocytes), ANP (atrial myocytes release this) – area of no Cx43/ANP but neurofilament staining = SAN
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6
Q

What makes SAN cells different from other cells?

A

electrical activity generating but do not contractile or conduct

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7
Q

How do SAN cells generate electrical activity?

A

Express HCN4 proteins – make up If channels (HCN4 proteins are not present in other areas of the heart), these channels are important for producing electrical activity

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8
Q

What are central SAN area surrounded by?

A

fibrosis/connective tissue:

  • SAN cells do not express connexins (e.g. Cx43, like atrial myocytes), has poor gap junction structure
  • This means SAN is electrically isolated from rest of heart.
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9
Q

Why is it important that SAN cells are electrically isolated from the rest of the heart?

A
  • Pacemaker potentials thought to leave SAN and spread to atrial through controlled specific pathways – currently unclear
  • Because it’s isolated SAN is not influenced by atrial electrical activity
  • Very important as atrial repolarisations would ‘switch-off’ SAN
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10
Q

How does the SAN generated pacemaker potential cause ventricular contraction?

A
  • SAN generated pacemaker potential and other action potentials generated by the electrical activity conducts out of the SAN into the surrounding atrial tissue.
  • Potential slows down as it goes into the atrio-ventricular node and it speeds up again as it passes through the bundle of His, the left and right bundle branches, purkinje fibres and ventricular muscle.
  • It causes a contraction in the ventricular tissue.
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11
Q

How does the SAN generated pacemaker potential make ECG patterns?

A

The co-ordinated stimulation and repolarisation of action potentials is what causes the ECG pattern.

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12
Q

what forms ionic basis for initiating pacemaker activity in the absence of external stimuli?

A
  • Activation of If channels initiates a diastolic depolarisation which forms the ionic basis for initiating pacemaker activity
  • There’s an unstable resting membrane potential – keeps generation action potentials
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13
Q

What happens in Phase 0?

A

Phase 0 is the activation of the upstroke – due to activation of voltage-gated Ca channels because Ca comes in, positively charged and causes an upstroke in the action potential

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14
Q

What happens in phase 3?

A

Phase 3 Ca channels switch off and K channels activate, and K moves out of the cell, down it’s concentration gradient, negative charge inside the cell – repolarisation

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15
Q

What happens in phase 4?

A

Phase 4 is the unstable resting membrane potential, If channels are activated.

If channels are hyperpolarisation activated non-selective channels - as the cell hyperpolarises and repolarises the If channels switch on and bring in Na

  • the cell becomes positive, starts depolarisation and that continues until threshold is reached for activation of voltage gated calcium channels
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16
Q

What do the different phases correlate with?

A

Different phases of the pacemaker potential relate to different phases of the heart – systole and diastole

17
Q

What does the voltage clock interact with?

A

The calcium clock

18
Q

What is the calcium clock?

A
  • rhythmic spontaneous sarcoplasmic reticulum Ca2+ release, feeds into voltage clock to cause initiation of action potential
  • Sarcoplasmic reticulum releases Ca through RyR, the calcium does several things:
    • Can be taken back up by SERCA
    • NaCa exchanger exchanges it for 3 Na, it gets taken out. The cell become more positive and causes depolarisation.

Calcium also comes in from L-type and t-type calcium channels – causes further activation of the NaCa exchanger and uptake of Ca into store

19
Q

What is the voltage clock?

A
  • cyclic activation and deactivation of membrane ion channels
20
Q

How do the voltage clock and the calcium clock interact?

A
  • A lot of calcium in the sarcoplasmic reticulum of the SAN cells
  • SERCA (sarcoplasmic reticulum calcium ATPase) pump uses ATP to take calcium up its concentration gradient, into the sarcoplasmic reticulum
  • ryanodine receptors are ligand gated ion channels, allow release of calcium from sarcoplasmic reticulum into cytoplasm
  • Voltage clock controlled by calcium channels (bring calcium in). If channels bringing in Na, and potassium channels for repolarisation
  • Ca clock feeds into it and initiates voltage clock through the sodium-calcium exchanger
21
Q

What is diastolic depolarisation

A

Normal cells have a stable resting potential during diastole

- SAN cells have diastolic depolarisation

22
Q

What are the ion channel interactions during diastolic depolarisation?

A

There’s a lot of important ion channel interactions that occur during diastolic depolarisation

  • K channels repolarise, become activated
  • If channels: Hyperpolarisation-activated cyclic nucleotide (HCN); activated at
23
Q

What are the phases of diastolic depolarisation?

A
  • Linear: If activation is polarising activating current, causes slow depolarisation in a linear scale
  • Non-linear: allows depolarisation threshold to be met earlier and there’s an exponential increase in depolarisation – caused by release of the “tick” Ca from RyR and NaCa exchanger which brings in Na ions which will cause increased depolarisation.

There’s also increased activity of T-type and L-type channel causes the upstroke after diastolic depolarisation

24
Q

Why are Ca signals bigger during upstroke?

A

Ca signals are bigger during upstroke because they are coming in through the L-type calcium channel

25
Q

Evidence about what comes first – Voltage or Ca2+ Clock?

A
  • There’s an increase in Ca signalling before action potential is generated – happens during the non-linear diastolic depolarisation and this suggests that Ca signal is generating another current (INaCa) which causes the non-linear diastolic depolarisation
  • After this there is a much larger upstroke – Ca is coming in through the opening of voltage gated Ca channels (l-type)
  • LCRs are localised Ca2+ releases
  • Not influenced by depolarisation
  • Occur during late diastolic depolarisation
26
Q

What determines speed of Ca2+ Clock – its ticks:

A
  • Speed of release/depletion of SR Ca2+ stores – RyR activity
  • Speed of SR Ca2+ recycling – SR SERCA activity
27
Q

What is the calcium clock influenced by?

A

Influenced by:

• Constitutive PKA activity (affects RyR)
o SAN express constitutively active adenylate cyclase isoforms
o Produces cAMP-mediated PKA phosphorylation of RyR
o Increases opening of RyR and greater release of Ca2+ from SR

• Pacemaker potential frequency (affects SERCA)
o More Ca2+ influx through T/L-type Ca2+ channels,
o Greater uptake of Ca2+ into stores
o More to be released

28
Q

Summary of evidence for Ca2+ Clock drives voltage Clock

A

1) Block of Ca2+ cycling
• Buffering [Ca2+]i to low levels slows/stops pacemaker activity

2) Block RyR
• reduced LCRs and reduced pacemaker potential frequency

3) Block L-type Ca2+ channels or prevent depolarisation
• reduced Ca2+ entry, reduced SR refilling, block LCRs, and pacemaker failure

29
Q

How are ryanodine receptor linked to rise in calcium?

A
  • Ryanodine - RyR inhibitor, stops localised ca release and there’s only linear diastolic depolarisation due to If channels
  • Action potential still produced but low frequency and takes longer to meet the threshold and produce upstroke
  • Proves ryanodine receptor is linked to a rise in calcium
30
Q

How is it proved that INCX (sodium calcium exhanger channels) are involved in diastolic depolarisation?

A
  • Li+ is a NCX (sodium calcium exhanger) inhibitor
  • Li blocks the NCX thus also blocks a current that triggers the non-linear diastolic depolarisation and the pacemaker potential is not made
  • INCX - involved in exponential increase in diastolic depolarisation
31
Q

What is seen in Cardiac-selective HCN4 KO mice? (they did not have If channels)

A
  • Decreased If currents
  • HCN4 KO produces bradycardia + death
  • Decreased Pacemaker Potential freq

If B1 (beta 1) receptors are stimulated it mimics the sympathetic system and causes an increase in HR

• B1 effect is via Ca Clock or other HCN channels and not If channels

32
Q

How do Sympathetic and Parasympathetic nervous systems alter rate of diastolic depolarisation

A

Sym - B1 - Gs - increase AC - increase cAMP – increase If – faster rate of diastolic depolarisation

  • Remember : increased cAMP leads to increased PKA activity, and PKA-phosphorylation of RyR induces more LCRs, evoking increased INCX

Parasym - M2 - Gi - decreased AC - decreased cAMP – decreased If – slower rate of diastolic depolarisation, will reduce heart rate

Remember: this will also reduce Ca2+ clock

33
Q

What are If channels mediated by?

A

If channels mediated by HCN proteins channels, they are clinical targets

34
Q

What do If channels do?

A

If channels – make ‘funny’ currents
• Activated by membrane hyperpolarisation, unique in vertebrates (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 can cause it – more If channels activates cause of it

35
Q

Where is HCN4 expressed in the heart and what is the knockout mouse phenotype for it?

A
  • Most found in SAN but also present in AVN (and His-Purkinje fibres)
  • K/O mouse phenotype: Varying (mild to marked) effects on cardiac automaticity; embryonic lethality
36
Q

How many types of HCN are there?

A

4

37
Q

what is Ivabradine?

A
  • A HCN modulator
  • Ivabradine is the 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 – reduction in heart rate
  • Oral, 50% bioavailability, metabolised by cytochrome P450 into active metabolite , half-life is 2 hours, metabolite is 13 hours
  • decreased heart rate by 10-20 beats/min in healthy individuals – good safety profile
38
Q

What is the clinical evidence for ivabradine?

A
  • INITIATIVE trial - Ivabradine not inferior to atenolol (beta blocker) to treat symptoms of stable angina
  • ASSOCIATE trial - add-on to beta-blockers, improved exercise duration

• SHIFT trial
o Class II/III NYHAS heart failure, EF<35%, >70 bpm, sinus rhythm
o Results All CV death decreased 1-2 %, Hospitalisations for HF decreased 26%
o Death from HF decreased 26%

SIGNIFY trial:
Study assessInG the morbidity-mortality beNefits of the If inhibitor Ivabradine in patients with coronarY artery disease
• End points reached of death from CV disease and non-fatal MI = unchanged
• No positive effect – different to SHIFT trial
• decreased HR too much, majority given too high dose (10 mg)
• Drug interactions with other drugs
• Difference in pathology of HF (heart failure) (SHIFT) vs. CAD (coronary artery disease) (SIGNIFY)

Cardio and Resp diseases (29 decks)

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