Lecture 3 - Cardiac Remodelling Flashcards
what are the major contributors to cardiac remodelling
- Myocytes
- Interstitium
- Fibroblasts
- Inflammatory cells
What is physiological remodelling
compensatory change in structure and function of heart in response to exercise / pregnancy
What is pathological remodelling
Changes that occur due to underlying disease. Begins as compensation and progresses to maladaptive
- HTN /heart valve disease /Post-MI/cardiomyopathy
Processes in cardiac remodelling
- Hypertrophy
- Apoptosis
- Fibrosis
- Inflammation
Explain eccentric hypertrophy
-volume overload–> physiologically ( endurance athletes ) / pathologically (valve disease )
Thin wall + large chamber size
Serial organization of sacromeres
Explain concentric hypertrophy
Pressure overload –> physiologically ( strength training) / pathologically ( HTN/aortic stenosis)
Thick wall + small chamber size
parallel organization of sarcomeres
Why does concentric remodelling occur post MI
maintain adequate cardiac output and counteract infarct expansion
What can infarct expansion lead to
eccentric hypertrophy and heart failure
What is different between physiological and pathological hypertrophy
In pathologoical hypertrophy there is:
fibrosis / apoptosis / inflammation/ fetal gene reactivation / irreversible/ increased glucose metabolism
What happens to metabolism in pathological hypertrophy
fatty acid oxidation to glucose metabolism
allows the heart to produce more ATP per molecule oxygen
Fetal gene program
response of the heart to haemodynamic / metabolic stress
-preference of glucose over fatty acids
Pathological pathway:
Initiating stimulus
Cardiomyopathy / disease
- activation of ATII / ET-1 / NE
- Bind to GPCR receptor on cell membrane
Pathological pathway:
Signalling pathways
GPCR activation leads to the release of GaQ
- this leads to the release of MAPKs / calmodulin / protein kinases C / calcineurin
Pathological pathway:
Cellular responses
- protein synthesis
- increased cell size
- gene expression
- fetal gene expression
- cardiac fibrosis
- cell death
Pathological pathway:
Cardiac function
depressed
Physiological growth:
stimulus
postnatal growth / excercise / pregnancy
- Growth factors –>IGF-1
- bind to RTK receptors
Physiological growth:
signalling pathways
RTK receptor activation
causes the release of PI3K (p110a)
-leads to the activation of Akt
Physiological growth:
Cellular responses
Gene expression
protein synthesis
increase in cell size
What is apoptosis
cell suicide –> used by the body to get rid of damaged cells beyond repair
-involves complex cascades of intracellular events and activation of protease enzymes
What does apoptosis do in the myocardium
increased apoptosis in myocytes contributes to progressive cardiac dysfunction in heart failure
Process of apoptosis
- cell damage triggers apoptosis
- cell shrinks / membrane remodelling/ chromatin condensation
- DNA fragmentation / membrane budding / signals emitted to attract macrophages
What are the two pathways in apoptosis
Intrinsic pathway ( mitochrondrial) Extrinsic ( death receptor pathway)
What is the extrinsic pathway induced by?
- extracellular signals –> ligands binding to specific receptors
- Fas receptors / TNFR1
- DISC complex is formed and caspase 8 activated
what is the intrinsic pathway induced by?
- DNA damaged /oxidative stress
- the mitochrondria releases cyt c which leads to the formation of the apoptosome and activation of caspase 9
Stage 1 Intrinsic pathway till BAX activation in cytosol
- DNA lesion
- ATM activation ( serine threonine kinase)
- p53 activaton
- PUMA activation ( p53 unregulated modulator of apoptosis )
Stage 2 intrinsic pathway till cytochrome C released in cytosol
- BAX activation in cytosol
- activated BAX becomes mitochondrial membrane bound
- opens channels in mitochondrial membrane
Stage 3 intrinsic pathway
- Cytochrome C released in the cytosol
- Cyt C + APAF-1 form apoptosome
- apoptosome cleaves procaspase 9 to caspase 9
- caspase 9 cleaves procaspase 3 to caspase 3
What does caspase 3 do?
- cleaves cytosolic and nuclear proteins
2. activates caspase activated DNase in the nucleus resulting in DNA fragmentation
What are the two pathways in extrinsic pathway
FAS pathway and TNFR1
What occurs in the FAS pathway?
- FasL receptors on cytotoxic T cell bind to FasR receptors
- This leads to the formation of DISC
- formation of DISC allows procaspase 8 to activate caspase 8 which activates caspase 3
What occurs in the TNFR1 pathway
- TNFa binds to TNFR1 receptor
- conformational change of receptors
- dissociation of SODD from receptor
- recruitment of TRADD + FADD
- cleavage of procaspase 8 to caspase 8
- clevage of procaspase 3 to caspase 3
Definition of fibrosis
excessive deposition of ECM proteins in particular collagen
What is reactive fibrosis
deposition of ECM proteins following haemodynamic stress
What is the aim of reactive fibrosis?
preserving cardiac output while normalizing wall stress
Reparative fibrosis
occurs post-MI space made between dead myocytes so collagen deposition to connect remaining heart cells –> provides support
What are the effects of fibrosis?
enhanced cardiac stiffness cardiac contraction affected arrhythmias cardiac dysfunction heart failure
Role of myocardial fibroblast in fibrosis?
increasing the production of collagen and other extracellular matrix proteins
1.What are the stimuli for cardiac fibrogenesis
Ischemia / MI / oxidative stress / mechanical stretch / HTN/ hormones
MYOCYTE DEATH
- What the stimulation of fibroblasts do?
proliferation and differentiation of fibroblasts
- What do fibroblasts differentiate into?
- ECM production
- myofibroblasts
- cytokine production
What is the result of fibroblast differentiation
reactive and reparative fibrosis
What happens after myocardial injury?
Infiltration by inflammatory cells
What two cells are involved in the infiltration?
Neutrophils and monocytes
What do neutrophils cause to be released
Cytokines (TNF-a) and MMPs
What does the release of cytokines cause?
activation of apoptosis
What does the release of MMPs cause?
degradation of collagen scaffold
What do monocytes cause the release of?
pro-fibrotic cytokines(TGF-B)
What do pro-fibrotic cytokines do?
stimulation of fibroblasts which causes myocardial fibrosis
What occurs in myocardial infarction
- occlusion of epicardial vessel
- oxygen/nutrient starvation
- myocyte necrosis
- myocyte necrosis
- myocyte death at infarct border –> infarct extention
What do the necrotic myocytes release?
DAMPs via TLRs
- attracts neutrophils/monocytes to the site
- leads to macrophages being present which clear necrotic tissue
What contributes to Infarct expansion?
neutrophils releasing proteases which degrade existing ECM
What does loss of myocytes and infarct expansion cause?
thinning of the ventricle wall and decrease in contractile function
How does the heart adapt to intensified wall stress?
scar formation in the infarct zone and cardiomyocyte hypertrophy in the non-infarcted region
What processes cause the adaption to intensitfied wall stress?
- Mechanical stretch
- neuro-hormonal activation
- increased symapthetic outflow
- RAAS activation
What the late remodelling consequences of MI
- Wall thinning
- dilation of ventricle
- spherical shape
- contractile dysfunction
What are the effects of reduced cardiac output?
- Activation of SNS
- reduction in renal blood flow–> activation of RAAS
how is the SNS activated by low CO?
- Low CO
- Fall in BP
- decreased firing of cartoid sinus + baroreceptors
- increased sympathetic out / reduced parasympathetic
- vasoconstriction/increased force of contraction/increased HR/increased BP
- further myocardial remodelling
how is the RAAS system activated
decrease in renal perfusion
Describe how ATII becomes activated
- Renin cleaves angiotensinogen produced by the liver to AT-1
- AT-1 is cleaved by ACE which is present in the lungs
- AT-2 formed
What does AT-2 do?
- Increased sympathetic nerve activity
- Aldosterone secretion ( Na+ reabsorption + water retention )
- endothelin release ( vasoconstriction + increased BP)
- ADH –> water absorption
What occurs as a result of AT-2 activation?
- water + salt retention
- effective circulating volume increase
What are the anti-remodelling therapies for heart failure
- Therapeutic interventions
- ACEi / ARBs / MRA
- reduce cell death/hypertrophy/fibrosis - GLP-1 - effective in treating metabolic derangements
- Mechanical support –> ventricular assist device
- limits ventricular dilation - cell replacement of cardiomyocytes
