changes in heart failure

Question 1

IK1 in HF

Answer 1

DEcreased: reduced IK1 channel density

=> AP prolongation, increased autoamticity

Question 2

what happens in overexpression of IK1?

Answer 2

acceleration and stabilisation of fibrillary rotors => shortens APD and cardiac wavelength => stabilises reentrant actiivty

Question 3

what does pharmacological reduction of IK1 do?

Answer 3

suppresses the dominant frequency of mother rotor that underlies arrrhythmias in structurally normal hearts =>promotes triggers, enhances automaticity

Question 4

delayed rectifiers in KF

Answer 4

Iks and Ikr are Decreased => prolonged APD
leads to EADs, conduction block and thus reentry
molecular mechanisms of downregulation are controversial
discrepant findings of HERG (Ikr) and KvLQT1 (IKs) expression => discrepancies highligh ion channel function as being dependent on several factors which go beyon the absolute quantities of channel subunit expression: i.e. post - translational modification, changes in protein assembly, trafficking, membrane insertion, degradation - all can modulate channel behaviour

Question 5

IKATP in HF

Answer 5

INCREASED => shortens ADP, increases conduction block

Question 6

If in HF

Answer 6

DEcreased in SAN, INcreased in the ventricles

Increases automaticity

Question 7

Na/K-atpase in HF

Answer 7

DEcreased => prolongs ADP, increases reverese NCX activity (Ca influx)

Question 8

Generally Na amounts in HF

Answer 8

are INcreased, which drives reverse NCX causing Ca overload and DADs

Question 9

Ito in HF

Answer 9

functionally DOWNregulated => shortens APD

Question 10

overall APD in HF

Answer 10

is prolonged

Question 11

ICa-L in HF

Answer 11

depends on the stage of HF:
ICa-L INCREASED in mild-moderate HF but DEcreased if mroe advanced
The response of ICa-L to Beta-AR stimulation is attenuated in HF, also rate-dependent potentiation is slowed, there is increased uncoupling, the inactivation is slowed
===> prolongs APD

Question 12

ICa-T

Answer 12

INcreased => electrical heterogeneity

Question 13

INCX

Answer 13

INCREASED => DADs

Question 14

INHE

Answer 14

increased in ischaemia and reperfusion injury

Question 15

SERCA2a

Answer 15

DECRREASED =>
decreased contractility
decreased relaxation
increqased APD
increased phosphorylation

Question 16

phospholamban in HF

Answer 16

decreased

Question 17

RyR2 in HF

Answer 17

Decreased =>
increased diastolic leak
increased phosphorylation
increased Ca waves

Question 18

outline the morphological changes in HF

Answer 18

Caardiomyocyte size and shape: hypertrophy, with specific characteristics dependent on aetiology of HF

surface topology - overall spatial disruption leading to delayed ECC coupling: loss of Z grooves, loss of t-tubules

intercellular communication - reduced electrical and functional coupling: Cx43 redistributed away from intercalated disks, reduced connexin expression]

EXtracellular matrix - fibroblasts driven by neurohormonal activation: increased fibroblast numbers, activation; increased production and deposition of ECM —> spatial uncoupling of cardiomyocytes, also arrhythmogenic substrate

Question 19

Functional changes in Heart failure:

Answer 19

1. Impaired B-AR signalling
2. abnormalities in Ca handlin
3. abnormalities in Na handling
4. mitochondrial dysfunction
5. increased apoptosis
6. abnormal gene expression

Question 20

outline impaired B-ar signaaalling

Answer 20

B1-Ar expression and density reduced, the ratio of B1 to B2 changes to 1:1 (from normal 4:1)
increased Gi:Gs coupling ratio for B2-ARs. this contributes to the B-AR desensitisation and is negatively inotropic on adrenergic stimulation

Question 21

details of Ca handling abnormalities:

Answer 21

1) downregulation of SERCA and reduced activity
2) sliglty downregulated PLB –> so SERCA:PLB ration overall is decreased.
3) elevated PP1 activity resulting in dephosphorylation of PLB (increasing its inhibitory activity of SERCA)
4) impaired CA reuptake and prolonged Ca transiets with smaller amplitude. Higher diastolic [Ca] in cytoplasm but reduced SR Ca stores in the SR lead to impaired contraction and relaxation
5) APD prolongation
Hyperphosphorylatio, increased oxidation of RyR2 causing Ca leak, increased Ca sparks
6) Increased NCX activity to extrude more Ca

Question 22

abnormalities in Na handling. details:

Answer 22

elevated intracellular [Na] due to (possibly):

1) reduced Na/K-atpase expression or activity - debatable
2) icnreased NCX, on the other hand, high [Na] may favour reverse mode, extrudin na and bringing in Ca
3) increased Na influx via NHE
4) Increased late Na current

This leads to:

1) increased reverse NCX, leading to high [Ca] cytosol (inefficient uptake to SR) –> DADs
2) disrupts ca uptake into mitochondria through mitochondrial NCX –> energetic inefficeincy, cell apoptosis
3) reduces the electrocheical gradient for H clearance by NHE, resulting in impaired acid-base balance

Question 23

details of mitochondrial dysfucntion

Answer 23

reduced phosphocreatine:ATP ration reflects imaired mitochondrial function

increased oxidative stress and ROS due to mitochondrial dysfucntion;
Effects of increased ROS:
1) increased SR Ca leak via RyR2 oxidation
2)impaired Na/K-atpase and SERCA activity
3) predisposition to apoptosis
4) self-generation of further ROS

Question 24

Increased apoptosis details:

Answer 24

due to a variety of factors:
increased mitochondrial ROS causes its dysfunction and eventual release of pro-apoptotic factors
Abnormal Ca handling may have a role in signalling factors that promote apoptosis

Question 25

abnormal gene expression details:

Answer 25

activation of fetal gene expression. results in physiology more akin to fetal myocardium:
switch from FFA metabolism to carbohydrates
changes in t-tubules and SR physiology
changes in sarcolemmal ion channel expression
alteration of myofilament heavy chain isoforms.