changes in heart failure Flashcards
IK1 in HF
DEcreased: reduced IK1 channel density
=> AP prolongation, increased autoamticity
what happens in overexpression of IK1?
acceleration and stabilisation of fibrillary rotors => shortens APD and cardiac wavelength => stabilises reentrant actiivty
what does pharmacological reduction of IK1 do?
suppresses the dominant frequency of mother rotor that underlies arrrhythmias in structurally normal hearts =>promotes triggers, enhances automaticity
delayed rectifiers in KF
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
IKATP in HF
INCREASED => shortens ADP, increases conduction block
If in HF
DEcreased in SAN, INcreased in the ventricles
Increases automaticity
Na/K-atpase in HF
DEcreased => prolongs ADP, increases reverese NCX activity (Ca influx)
Generally Na amounts in HF
are INcreased, which drives reverse NCX causing Ca overload and DADs
Ito in HF
functionally DOWNregulated => shortens APD
overall APD in HF
is prolonged
ICa-L in HF
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
ICa-T
INcreased => electrical heterogeneity
INCX
INCREASED => DADs
INHE
increased in ischaemia and reperfusion injury
SERCA2a
DECRREASED => decreased contractility decreased relaxation increqased APD increased phosphorylation
phospholamban in HF
decreased
RyR2 in HF
Decreased =>
increased diastolic leak
increased phosphorylation
increased Ca waves
outline the morphological changes in HF
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
Functional changes in Heart failure:
- Impaired B-AR signalling
- abnormalities in Ca handlin
- abnormalities in Na handling
- mitochondrial dysfunction
- increased apoptosis
- abnormal gene expression
outline impaired B-ar signaaalling
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
details of Ca handling abnormalities:
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
abnormalities in Na handling. details:
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
details of mitochondrial dysfucntion
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
Increased apoptosis details:
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
abnormal gene expression details:
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.
