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

LQT Syndrome and EC Coupling in HF Flashcards

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
Q

Where else is pressure overload seen?

A

aortic stenosis or hypertension

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26
Q

What must the heart do in pressure overload?

A

pump blood out at a higher pressure

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27
Q

What happens in volume overload?

A

there is aortic or mitral valve regurgitation - causes volume stress and the heart to dilate

28
Q

What happens if the aortic valve fails to close properly?

A

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
Q

What can cause contractile dysfunction?

A

ischemic heart disease
myocardial disease
congenital myopathies

30
Q

What is the issue with contractile dysfunction?

A

the heart is unable to receive enough oxygen to function adequately as a pump

31
Q

What happens with left ventricular hypertrophy?

A

smaller chamber -> reduced SV-> reduced CO

greater oxygen demand for the same CO

32
Q

What happens with the growth of muscle in hypertrophy?

A

the growth of the heart outstrips its growth of arteries and capillaries

33
Q

What can the l.ventricular hypertrophy lead to?

A

focal ischemia, fibrosis and collagen deposition

34
Q

What is the result of the supply/demand imbalance in hypertrophy?

A
  • stiffer heart which is harder to beat
  • exacerbated dilation /increased wall stress -> more failure
  • vicious cycle
35
Q

What does HF start with?

A
  • muscle overload leading to hypertrophy

- coronary artery disease leading to reduced blood supply

36
Q

What is hypertrophy?

A

an adaptive change which can compensate for many years but eventually lead to l.v dysfunction, dilation and failure

37
Q

What can be seen further in heart failure?

A
  • reduced ejection fraction
  • expression of fetal genes
  • myocyte loss
38
Q

What did Gomez et al. find when looking at cardiac hypertrophy in hypertensive rats?

A
  • same inward Ca current caused smaller Ca transient
  • sparks were indistinguishable from normal rats
  • but spark frequency lower in hypertrophied hearts
39
Q

What can be seen with uncoupling of the LTCC and RyR?

A

physical increase in dyadic cleft -> so RyR sees less calcium and opens less -> decreased contractile function

40
Q

What happens when the RyR sees less Ca?

A

decreased contractile function due to impaired CICR

41
Q

What is prolonged in HF?

A

the AP and the Calcium transient

42
Q

Why are there changes in the cellular processes leading to contraction?

A

due to a failed attempt to increase contractility and a reversion to foetal gene expression

43
Q

When can Ca uptake and extrusion compromisation be seen?

A

apparent when HR increases and myocytes are unable to relax

44
Q

what occurs in addition to a decrease in force production?

A

diastolic dysfunction

45
Q

What happens in diastolic dysfunction?

A

the heart fails to fill with blood properly between beats - doesn’t matter how much force it can generate

46
Q

What happens with AP and Ca transient in HF?

A

no longer synchronised - not too bad in moderate HF but in severe the transient is very prolonged

47
Q

What is APD prolongnation due to?

A

decreased repolarising currents

increased depolarising inward currents

48
Q

What channels are involved with the decrease in repolarising currents?

A

Ito, IK1, IKs, IKr

49
Q

What contributes to the increased depolarising currents?

A

background Na
NCX
TTCC

50
Q

Why are additional depolarising currents an issue in HF?

A

NCX can increase IC Na and that can generate another AP -> arrhythmias

51
Q

What are the potential reasons for the SR Ca decrease in release?

A

either less Ca in SR or trigger isn’t as effective - probs both

52
Q

What did O’Rourke et al. do to discover why Ca uptake into the SR is reduced?

A

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
Q

What other calcium extrusion mechanism is the failing heart dependent on?

A

NCX

54
Q

Why does NCX block cause issues in HF animals?

A

the Calcium can’t get out - there is an increase in depolarising currents which causes issues with Ca extrusion

55
Q

What can be seen in HF?

A

Less SERCA 2A and PLB

Lots more NCX

56
Q

Why is relaxation slowed in HF?

A

main calcium extrusion mechanism is wiped out

57
Q

Why are failing cells less responsive to inotropes i.e. adrenaline?

A

because they are unable to shorten the contractile cycle

58
Q

What is the consequence in the failing human heart on the force-frequency relationship?

A

force decreases with increased frequency because heart can’t respond to exercise or b-adrenoceptor stimulation

59
Q

What happens in order for the heart to maintain CO in HF?

A

ends up with a large EDV

60
Q

What does an increase in EDV cause?

A

increase in atrial filling pressure -> increased hydrostatic pressure in lung -> fluid accumulation

61
Q

What are the compensatory changes in the failing heart?

A

increase NCX and increased myofilament sensitivity

62
Q

What was the results of in vivo SERCA therapy?

A

improved ejection fraction
improved rate of force generation
improved relaxation (tau)
improved performance at multiple pacing rates and improved survival

63
Q

What are the results of SERCA Gene therapy in humans?

A

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
Q

What are the global adaptations for HF?

A

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
Q

What are the first line treatments in HF?

A

b-blockers
ACE Inhibitors
Diuretics

Cardiovascular Pharmacology (7 decks)

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