Cardiac Remodelling Flashcards
(28 cards)
What is cardiac remodelling?
The alteration in the structure (dimensions, mass, shape) of the heart in response to changes in hemodynamic load (i.e. increased pressure or blood volume) and/or cardiac injury
Therefore a change in function of the heart
Hemodynamic load/cardiac injury -> molecular, cellular and/or intersititial changes -> change in size/shape/function of the heart
What are the 4 main contributors to cardiac remodelling?
Myocyte - main contractile unit of the heart
Fibroblasts - supporting cells, role in physiology and pathology
Interstitium - from the external matrix e.g. collagen
Inflammatory cells
What are the types of cardiac remodelling?
Physiological
A compensatory change in the dimensions and function of heart in response to physiological stimuli e.g. pregnancy and exercise - “athlete’s heart“
Pathological Changes that may occur with: High blood pressure i.e. hypertension Heart valve disease Following myocardial infarction Cardiomyopathy (dilated and hypertrophic) - often may transition from a compensatory process to a maladaptive one
What are some processes involved in cardiac remodelling?
Hypertrophy - change in myocyte size
Apoptosis - programmed cell death
Fibrosis - excessive extra cellular matrix deposition - notably collagen
Inflammation
Describe the types of hypertrophy that can lead to cardiac remodelling?
Eccentric
Occurs from volume overload
- Physiological - endurance training (swimming/running)
- Pathological - valve disease
Characteristics - thin wall and large chamber size
The cardiomyocyte ‘stretch’ and look longer
At a cellular level - serial organisation of sarcomeres
Concentric
Occurs from pressure overload
- Physiological - strength exercise (weight training)
- Pathological - high BP and/or aortic stenosis
Characteristics - thick wall and small chamber size
The cardiomyocytes have increased in height
At a cellular level - parallel organisation of sarcomeres
What type of hypertrophy occurs after a heart attack?
Following a heart attack (myocardial infarction) – both forms of hypertrophy may be evident:
Either can take place to counteract the effects but both tend to lead to heart failure
Describe the pathways involved in hypertrophy?
Pathological:
Stimulus - cardiomyopathy, disease
Neurohormones are activated from the stimulus - they interact with G-protein coupled receptors
Triggers intracellular signalling
Cellular responses - change in protein synthesis, gene expression, fibrosis, cell size, cell death
Cardiac function - depressed
Physiological:
Stimulus - exercise, post natal growth
Growth factors are activated from the stimulus - they interact membrane receptors
Triggers intracellular signalling
Cellular responses - change in protein synthesis, gene expression, cell size
Cardiac function - normal or enhanced
Give a comparison of phsiological/pathological hypertrophy?
Both increase protein synthesis
Physiological - increased fat metabolism
Pathological - decreased fat metabolism and increased glucose metabolism
Heart performance
Physiological - increased
Pathological - increased initially
Physiological - reversible
Pathological - irreversible
Describe apoptosis?
AKA programmed cell death (PCD)
This is cell suicide - used to rid the body of cells that have been damaged beyond repair
This involved complex cascades of intracellular events and activation of protease enzymes (caspases)
Increased apoptosis with loss of myocytes contributes to progressive cardiac dysfunction in heart failure
In myocardial samples from patients who underwent heart transplantation, apoptosis was increased more than 200-fold in the failing heart
What is significant about apoptotic cells?
They are biochemically recognisable
An endonuclease cleaves the chromosomal DNA into fragments
The phosphatidylserine, normally on the inner leaflet, flips to the outer leaflet - and can serve as a marker
This marker also blocks inflammation and therefore cytokines
Give an overview of the mechanism of apoptosis?
- Cell damage, stress or signal triggers apoptosis
- Cell shrinkage, membrane remodelling and chromatin condensation
- DNA fragmentation, membrane budding - emits signals to attract macrophages
- Apoptotic body formation
- Phagocyte engulfs the apoptotic bodies
What are the different pathways involved in apoptosis?
Extrinsic pathway – referred to as the death receptor pathway
Induced by extracellular signals - upon ligand binding to specific receptors (e.g. Fas, TNFR1) the DISC complex (death initiation signalling) is formed and caspase 8 activated
This cleaves caspase 3 into its active site - which brings about apoptosis
Intrinsic pathway – the mitochondrial pathway
Activated following e.g. DNA damage, oxidative stress = release of Cytochrome c from the mitochondria
Cytochrome C binds to APAF-1 (apoptosis protease-activating factor-1)
This recruits procaspase 9 to form a apoptosome
Procaspase 9 is cleaved to caspase 9, which cleaves caspase 3 into its active site - which brings about apoptosis = cell death
Describe the extrinsic pathway of apoptosis?
Extracellular signal proteins bind to cell-surface death receptors that trigger the this pathway
Death receptors are transmembrane proteins (homodimers) containing a death domain
When activated the death domains recruit intracellular adaptor proteins which then recruit procaspases forming a death-inducing signalling complex (DISC)
Once activated DISC induces initiator caspases to activate downstream executioner procaspases to induce apoptosis
What are the two types of extrinsic pathways within apoptosis?
FAS pathway
Cytotoxic T-cell containing FasL binds to Fas receptor which contains a FADD (death domain)
This activates procaspase 8, which is cleaved into caspase 8
The caspase cascade leads to procaspase 3 being cleaved into caspase 3 - which leads to cell death
TNFR1 pathway
TNFa binds to TNFR1 receptor - which gives a conformational change
There is dissociation of SODD (silencer of death domain) from receptor
TRADD is recruited, leading the recruitment of FADD
This gives the cleavage of procaspase 8 to caspase 8 and then cleavage of procaspase 3 to caspase 3 = 3 cell death
Describe the intrinsic pathway of apoptosis?
When cytochrome c is released into the cytosol
It binds to an adaptor protein Apaf1 (apoptotic protease activating factor)
This forms a multi-molecular heptamer complex - apoptosome
This recruits initiator proteins - procaspase-9
This activates downstream executioner procaspases
The caspase cascade then leads to apoptosis
Describe fibrosis and how it leads to cardiac remodelling?
Definition: Excessive deposition of extra cellular matrix (ECM) proteins (in particular collagen)
Fibrosis overall causes enhanced stiffness of the heart, impedes cardiac contraction and relaxation, arrhythmias, cardiac dysfunction - heart failure
Reactive fibrosis
Deposition of ECM proteins following hemodynamic stress (e.g. hypertension), is an adaptive response aimed at preserving cardiac output while normalizing wall stress
Reparative fibrosis
Following a heart attack (MI) dead cardiomyocytes leave empty spaces so collagen deposition occurs to connect remaining heart cells - provides support
Describe cardiac fibrogenesis cascade?
Stimulus - ischemia, MI, oxidative stress, mechanical stress, hypertension and hormones
This causes proliferation and differentiation
They can be differentiated into myofibroblasts, ECM production and cytokine production
Describe inflammation’s role in cardiac remodelling?
After myocardial injury = influx of inflammatory cells
First neutrophils - they produce cytokines (activation of apoptosis) and MMPs (degradation of collagen scaffold)
Later macrophages - they release pro-fibrotic cytokines, leading to the stimulation of fibroblasts - this leads to myocardial fibrosis
What can also happen to the heart other than hypertrophy?
Atrophy - degradation of the heart muscle occurs on bed rest and in space
What is the role of neuro-hormonal response in remodelling?
‘When good intensions go bad’
After a MI, there is reduced cardiac output and therefore less BP
This activates the sympathetic nervous system, decrease parasympathetic system and also causes reduction in renal blood flow
The increase in BP from: increased HR, vasoconstriction, increased peripheral resistance and increased cardiac output can then cause further myocardial remodelling/damage
Reduction in renal blood flow = activation of RAAS - Renin Angiotensin Aldosterone System
This causes the release of renin from juxtaglomerular cells in the kidney
Renin leads to conversion of angiotensinogen into angiotensin I
Angiotensin I is converted by ACE into angiotensin II = proto-vasoconstrictor
Describe angiotensin II?
Causes constriction of blood vessels and therefore increases BP (it releases endothelin that does this as well)
It causes the release of aldosterone - causes the tubular reabsorption of Na+ and water retention
It allows secretion of anti-diuretic hormone (from pituitary gland) = water absorption
Due to water and salt retention - effective circulating volume increases
Increase in BP = further adverse effects
What are some anti-remodelling therapies for heart failure?
- Therapeutic interventions - ACE inhibitors and angiotensin receptor blockers
- Glucagon like peptide-1 - stimulates myocardial uptake of glucose and could sustain LV function
- Ventricular assist device - mechanical support
- Cell replacement therapy - replenish lost cardiomyocytes (experimental but promising)
Describe the composition of the extracellular matrix (ECM)?
It can vary but is generally composed of 4 major types of molecules:
1. Structural Proteins
Collagen and Elastin
- Adhesion Glycoproteins
Fibronectin and Laminin - Glycosaminoglycans (GAGs) and Proteoglycans
Hyaluronan, Heparan and Dermatan Sulfate - Matricellular Proteins
Thrombospondins, Osteopontin and Tenascin C
No structural role
Act as biological mediators of cell function i.e. regulate cell matrix interactions
What is the role of Tenascin C in post infarct remodelling?
Tenascin C (TNC) is an extracellular matrix protein Each TNC monomer comprises 4 distinct domains: assembly domain (TA), EGF-L repeats, conserved and alternately spliced It also contains a C-terminal fibrinogen globe
It is expressed in the heart during its development but is not expressed in adult hearts
It re-appears in the adult heart following injury (e.g. myocardial infarction, hypertension, myocarditis) - pathological conditions
