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Cardiovascular Pharmacology > LQT Syndrome and EC Coupling in HF > Flashcards

LQT Syndrome and EC Coupling in HF Flashcards

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1
Q

What is responsible for IKs?

A

KCNQ1

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2
Q

What directs PKA to KCNQ1?

A

Yotiao

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3
Q

Where is KCNQ1 phosphorylated by yotiao?

A

serine 27

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4
Q

Where is yotiao phosphorylated?

A

serine 43

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5
Q

What is LQT Syndrome?

A

a fatal arrhythmia where there is delayed repolarisation usually brought on by exercise

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6
Q

Why is the AP longer in LQT syndrome?

A

K current is slower to activate

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7
Q

How is LQT Syndrome diagnosed?

A

QT prolongnation with an Adrenaline infusion

family history of sudden cardiac death

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8
Q

What is the treatment for LQT syndrome?

A

b-blockers

implantable cardioverter-defibrillator

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9
Q

What is LQT1 caused by?

A

mutations in KCNQ1

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10
Q

Why does the AP get longer in LQT during adrenergic stimulation?

A

the activating depolarising current prolongs the AP

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11
Q

What mutation is responsible for lethality through failed recruitment of the AKAP?

A

G589D

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12
Q

What is the issue in G589D?

A

Yotiao can no longer bind and phosphorylate serine 27

KCNQ1 cannot be activated by cAMP

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13
Q

Which mutation in yotiao causes LQT?

A

S1570L - AKAP fails to find KCNQ1

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14
Q

What is the main feature of the S1570L mutation?

A

heterozygous mutants aren’t affected the same

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15
Q

Where do mutations in LQT1 come from?

A

IKs

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16
Q

What is the incidence of LQT1?

A

30-35% cases

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17
Q

Where do mutations occur in LQT2?

A

IKr (HERG)

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18
Q

What is the incidence of LQT2?

A

25-30%

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19
Q

Where do mutations occur in LQT3?

A

SCN5A mutations

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20
Q

What occurs in LQT3?

A

Nav opens late in the AP, so channel doesn’t remain inactivated - additional depolarisation prolongs AP

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21
Q

What is Heart Failure defined as?

A

an inability to provide sufficient cardiac output to supply the metabolic demands of the organism OR can only do so at the expense of raised filling pressure

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22
Q

What is the 5 year survival for HF diagnosis?

A
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23
Q

What happens in HF?

A

start to express fetal heart genes

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24
Q

What are the 3 primary causes of HF?

A
  • pressure overload
  • volume overload
  • contractile dysfunction
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25
Where else is pressure overload seen?
aortic stenosis or hypertension
26
What must the heart do in pressure overload?
pump blood out at a higher pressure
27
What happens in volume overload?
there is aortic or mitral valve regurgitation - causes volume stress and the heart to dilate
28
What happens if the aortic valve fails to close properly?
blood leaks back into the heart -> reduction in arterial pressure activates baroreceptor -> increase sympathetic stimulation to restore pressure and RAAS activation to increase blood volume
29
What can cause contractile dysfunction?
ischemic heart disease myocardial disease congenital myopathies
30
What is the issue with contractile dysfunction?
the heart is unable to receive enough oxygen to function adequately as a pump
31
What happens with left ventricular hypertrophy?
smaller chamber -> reduced SV-> reduced CO | greater oxygen demand for the same CO
32
What happens with the growth of muscle in hypertrophy?
the growth of the heart outstrips its growth of arteries and capillaries
33
What can the l.ventricular hypertrophy lead to?
focal ischemia, fibrosis and collagen deposition
34
What is the result of the supply/demand imbalance in hypertrophy?
- stiffer heart which is harder to beat - exacerbated dilation /increased wall stress -> more failure - vicious cycle
35
What does HF start with?
- muscle overload leading to hypertrophy | - coronary artery disease leading to reduced blood supply
36
What is hypertrophy?
an adaptive change which can compensate for many years but eventually lead to l.v dysfunction, dilation and failure
37
What can be seen further in heart failure?
- reduced ejection fraction - expression of fetal genes - myocyte loss
38
What did Gomez et al. find when looking at cardiac hypertrophy in hypertensive rats?
- same inward Ca current caused smaller Ca transient - sparks were indistinguishable from normal rats - but spark frequency lower in hypertrophied hearts
39
What can be seen with uncoupling of the LTCC and RyR?
physical increase in dyadic cleft -> so RyR sees less calcium and opens less -> decreased contractile function
40
What happens when the RyR sees less Ca?
decreased contractile function due to impaired CICR
41
What is prolonged in HF?
the AP and the Calcium transient
42
Why are there changes in the cellular processes leading to contraction?
due to a failed attempt to increase contractility and a reversion to foetal gene expression
43
When can Ca uptake and extrusion compromisation be seen?
apparent when HR increases and myocytes are unable to relax
44
what occurs in addition to a decrease in force production?
diastolic dysfunction
45
What happens in diastolic dysfunction?
the heart fails to fill with blood properly between beats - doesn't matter how much force it can generate
46
What happens with AP and Ca transient in HF?
no longer synchronised - not too bad in moderate HF but in severe the transient is very prolonged
47
What is APD prolongnation due to?
decreased repolarising currents | increased depolarising inward currents
48
What channels are involved with the decrease in repolarising currents?
Ito, IK1, IKs, IKr
49
What contributes to the increased depolarising currents?
background Na NCX TTCC
50
Why are additional depolarising currents an issue in HF?
NCX can increase IC Na and that can generate another AP -> arrhythmias
51
What are the potential reasons for the SR Ca decrease in release?
either less Ca in SR or trigger isn't as effective - probs both
52
What did O'Rourke et al. do to discover why Ca uptake into the SR is reduced?
Used CPA which blocks SERCA and thus uptake into the SR | In normal hearts CPA block is really big but much smaller in HF hearts so suggests that less SERCA available
53
What other calcium extrusion mechanism is the failing heart dependent on?
NCX
54
Why does NCX block cause issues in HF animals?
the Calcium can't get out - there is an increase in depolarising currents which causes issues with Ca extrusion
55
What can be seen in HF?
Less SERCA 2A and PLB | Lots more NCX
56
Why is relaxation slowed in HF?
main calcium extrusion mechanism is wiped out
57
Why are failing cells less responsive to inotropes i.e. adrenaline?
because they are unable to shorten the contractile cycle
58
What is the consequence in the failing human heart on the force-frequency relationship?
force decreases with increased frequency because heart can't respond to exercise or b-adrenoceptor stimulation
59
What happens in order for the heart to maintain CO in HF?
ends up with a large EDV
60
What does an increase in EDV cause?
increase in atrial filling pressure -> increased hydrostatic pressure in lung -> fluid accumulation
61
What are the compensatory changes in the failing heart?
increase NCX and increased myofilament sensitivity
62
What was the results of in vivo SERCA therapy?
improved ejection fraction improved rate of force generation improved relaxation (tau) improved performance at multiple pacing rates and improved survival
63
What are the results of SERCA Gene therapy in humans?
improved ejection fraction at 6,9,12 months but only in med/high doses fewer non-terminal CV events after 3 years and better 3 year survival
64
What are the global adaptations for HF?
collagen disposition in EC matrix - stiffer muscle, impaired relaxation increased sympathetic drive via baroreceptor reflec activation of RAAS - Na and water retention -> increased BP
65
What are the first line treatments in HF?
b-blockers ACE Inhibitors Diuretics

Cardiovascular Pharmacology (7 decks)

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