HF from Scientific Perspective Flashcards
Similarities of HF and COPD
- Primary symptom is breathlessness
- Possibly much misdiagnosis of one as the other
- Sx associated with many of the chronic diseases of old age (including Alzheimer’s)
- Cachexia, vascular disease
Primary damage
- MI (~50%)
- Valve disease
- Genetic defects
- Alcohol
- Drugs (cardio-toxic chemotherapy - anthracyclines)
- HTN (poorly controlled)
Natural Hx of HF
- Primary injury causing initial damage
- Apparent recovery/compensation
- Decompensation (HF syndrome, Sx)
- Death (poor survival)
Factors of Apparent recovery
- Hypertrophy
- Dilatation (increases filling to preserve CO with rEF)
- Volume loading (fluid retention)
- Sympathetic stimulation
Why does the body respond in the way it does
- (Harris P et al. CVR 1983)
- Chronic activation of ancient evolutionary reflex for acute problem exercise/haemorrhage
- Exercise (make heart pump harder)
- Haemorrhage (retain fluid)
How CMs die
- Catastrophic cell death (necrosis)
- Necroptosis (TNF-alpha mediated, as in sepsis)
- Controlled cell death (apoptosis or autophagy)
Necrosis
- Usually results from Ca overload due to membrane rupture
- Myofilaments hyper contract and buckle over each other
- Cell contents released (prolongs damage)
- Mitochondrial DNA may trigger pyroptosis (similar to infection response)
Apoptosis
- Mitochondrial eM changes
- Bad/Bax and Cas-3 signalling - Cell shrinkage/ Chromatin condenses
- Membrane blebbing starts
- Nucleus collapses, blebbing continues
- Apoptotic bodies form
- ABs are lysed or phagocytosed to prevent spilling of cell contents
Autophagy
Method of recycling of cell/contents
- Double membrane formed around contents
- Lysosomes formed/recruited
- Merging of vesicles and lysosomes
- Contents digested and recycled
Importance of autophagy
- Needed for plasticity (changing cell functionality)
- Blocking it reduces the heart’s ability to remodel with unloading
(Oyabu J et al. Biochem Biophys Res Comms 2013)
Genetic Cardiomyopathies
- Mechanisms
- Mutation may damage heart directly
- Continual ER stress due to misfolded proteins
- Mild depression of function causing a life-long endocrine response/insult
Titin Truncation
- May explain almost all idiopathic DCM
- May increase risk of HF in context of another insult eg. alcohol stress
The remaining CMs in HF
- Morphology
- Longer/wider (sarcomeres added in series or parallel)
- More branched
HF CMs
- Force-frequency
- Contraction
- Relaxation
- Reduced Treppe phenomenon
- Reduced contraction aptitude
- Relaxation impaired (poor Ca control), hence lower contraction amplitude
Is change in size the cause of APD increase?
Harding SE et al. 1994, 1995
Normal sized HFCMs function worse than large CMs from normal hearts
Ion currents in HF and APD
- Ik(s) and Ik(r) are small/absent
- Ik1 decreased
- I(to) epi:endo reduced
- Na/K-ATPase decreased
- SERCA2a decreased (less PL-Pi)
- NCX increased (competes for Ca with SERCA2a)
Plasma NOR
- Independent predictor of mortality
- Increases with B-AR desensitisation
- More needed to produce the same +ve inotropy
B-AR signal
- Gs dissociation to B-gamma and alpha-s
- alpha-s activates adenylate cyclase to increase cAMP
B-AR signal inhibition
M2-R
-Gi dissociates to B-gamma and alpha-i
- B-gamma mops up the alpha-s by mass action
- alpha-i can inhibit cAMP (not main component in heart)
B-AR sequestration
- Stimulated BA-R release B-gamma
- BA-R-Kinase 1 (GRK2) is attracted to membrane by
B-gamma protein - GRK2 Pi BA-R
- BA-R.Pi binds to arrestin and is recycled
Foetal Gene Program
- CMs return to a FGP in sustained hypoxia in an attempt to reduce stress on the heart
- Results in reduced CO
- Individual CM contractility reduces in the long term
Factors of Ca Handling
- Increased in HF
- NCX
- RyR/L-TCaC Pi
- Gi
- P38MAPK
Factors of Ca Handling
- Decreased in HF
- Na/K-ATPase
- SERCA2a
- I(to)
- Myofilament Pi
Energy Deficit in HF
- Heart is chronically under a challenging load, that contributes to the HF phenotype
- Phosphocreatine:ATP is a good indicator of disease
Regeneration in the heart
Bergmann. Science 2009
- C14 carbon dating shows 50% of CMs are present at birth
- ~1% turnover at 25
- ~0.45% turnover at 70
- So some low-level regeneration occurs
- Insufficient to replace large cell loss after MI
Plasticity
- Heart relies on changing the existing CMs more than growing new ones to respond to injury
- Possibly because it cannot tolerate apoptosis/structural changes on a large scale and keep beating
Max Force
- Reduced in HF
- More stimulation but less force
