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Pumps, Pipes and Electrics > Cardiac Remodelling in Disease-Mechanisms of Cardiac Remodelling > Flashcards

Cardiac Remodelling in Disease-Mechanisms of Cardiac Remodelling Flashcards

1
Q

What is cardiac remodelling?

A

Alterations to the structure (dimensions, mass and shape) of the heart and thus its function in response to changes in haemodynamic load e.g increased pressure or volume, or because of cardiac injury

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2
Q

What are the steps in cardiac remodelling?

A
  1. Altered haemodynamic load or cardiac injury
  2. Molecular changes (altered gene expression)
    - Cellular changes (altered myocyte form)
    - Interstitial changes (altered extracellular matrix)
  3. Change in size, shape and function of the heart
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3
Q

In what two ways can the heart respond to stimuli?

A
  1. GROWTH/HYPERTROPHY-can be caused by pathology or physiology e.g exercise
  2. SHRINKAGE/ATROPHY-e.g prolonged bed rest, astronauts with zero gravity, injured athletes
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4
Q

What is physiological remodelling?

A

a compensatory change to the dimensions and functions of the heart in response to physiological stimuli e.g exercise, pregnancy

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5
Q

What is pathological remodelling?

A

Change to the hearts dimensions and function because of pathological stimuli-this remodelling is usually NOT BENEFICIAL where as physiological remodelling is.
Causes of pathological remodelling include:
1. Pressure overload e.g Hypertension
2. Volume overload e.g Heart valve disease (regurgitation)
3. Cardiac injury e.g MI-induced ischaemia

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6
Q

Is pathological remodelling beneficial?

A

At first, pathological remodelling is usually compensatory and is therefore beneficial, however if the pathological stimulus persists this remodelling generally becomes maladaptive

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7
Q

What can pathological remodelling lead to?

A

It can lead to the development of heart failure

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8
Q

What therapeutics can be used to help pathological remodelling?

A
  1. Drugs such as ACEi’s and B-blockers
    - these drugs improve heart failure outcomes and can reverse some remodelling
    - These drugs can also relieve the stimulus that is causing the remodelling i.e Hypertension
  2. LVADs-ventricular assist devices have shown marked improvement in cardiac performance in patients with advanced heart failure
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9
Q

What are the major cell types involved in cardiac remodelling?

A
  1. FIBROBLASTS-these cells make up 2/3 of cardiac cells
  2. INTERSTITIUM-the extracellular matrix
  3. COLLAGEN-a component of the extracellular matrix
  4. MYOCYTE-the muscle cells of the myocardium
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10
Q

What are the four processes involved in cardiac remodelling at a glance?

A
  1. HYPERTROPHY-enlargement of myocytes
    - these muscle cells are terminally differentiated so they cannot replicate.
    - this means that in order to increase the size of the heart, these cells must increase in size
  2. FIBROSIS-excess deposition of collagen in the ECM
  3. APOPTOSIS
  4. INFLAMMATION
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11
Q

What is Eccentric Hypertrophy?

A

An increase in the size of the heart caused by VOLUME OVERLOAD
-Myocytes increase in size LENGTH ways by the addition of sarcomeres in series
-This lengthening of myocytes means they also get thinner so the ventricle becomes dilated with a relative thinning of the wall
-Physiological stimuli that cause this type of hypertrophy include endurance/isotonic exercise such as running, cycling and swimming in which volume overload occurs
Pathological stimuli include conditions where volume is increased for example aortic regurgitation where EDV increases (blood regurgitates from the aorta but the usual amount of blood is still put in from the atria)

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12
Q

What is concentric hypertrophy?

A

a change in the size and function of the heart caused by PRESSURE OVERLOAD

  • this type of remodelling shows myocytes getting wider through the addition of sarcomeres in parallel
  • This fattening of myocytes shows a thickening of the ventricular wall and a resultant decrease in the volume of the ventricular chamber
  • It is caused by stimuli that produce pressure overload
  • this can be VIS A FRONTE with pressurised preload
  • or can be VIS A TERGO with increased afterload
  • Physiological stimuli that induce pressure overload include strength training/isometric exercise in which blood pressure is increased
  • Pathological stimuli include Hypertension (increased afterload and preload) or Aortic Stenosis (heart has to squeeze harder against the resistance of the valve)
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13
Q

What happens in mixed hypertrophy?

A

The hypertrophy that occurs in the remote, non-infarcted myocardium as part of the normal remodelling process following MI can be both eccentric and concentric.

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14
Q

Do both types of hypertrophy show myocyte size increase?

A

Yes

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15
Q

Do both types of hypertrophy show fibrosis?

A

No-pathological does but physiological DOES NOT

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16
Q

Which type of hypertrophy shows apoptosis?

A

Pathological

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17
Q

Which hypertrophy shows Foetal Gene Expression?

A

Pathological

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18
Q

Which hypertrophy shows increased protein expression?

A

Both-both types need to increase protein synthesis in order to be able to grow their myocytes

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19
Q

What happens to metabolism in physiological remodelling?

A

Metabolism remains based upon fatty acids (normal for cardiac tissue) but the level of metabolism increases

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20
Q

What happens to metabolism in pathological remodelling?

A

It moves away from fatty acid metabolism and uses glucose instead

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21
Q

Does heart performance increase in both types of remodelling?

A

Heart performance increases in physiological remodelling.

In pathological, heart performance increases initially but then begins to fail

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22
Q

Are both types of remodelling reversible?

A

Physiological IS reversible but pathological IS NOT

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23
Q

What is meant by foetal gene expression in pathological remodelling?

A

In pathological remodelling the myocytes appear to re-express foetal cardiac genes that express ANP, BNP and aMHC
-This seems to induce some of the alterations seen or induces the change in metabolism but in reality this mechanism remains rather unclear

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24
Q

How does a myocyte normally metabolise?

A

Myocytes usually use:
-60-80% fatty acid oxidation
-20-40% Glucose, Lactate and Ketones
^The heart is able to switch between its substrates depending on nutritional status and hormones

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25
Q

Why do pathological myocytes switch from fatty acid oxidisation to glucose metabolism?

A

Glucose metabolism uses up less oxygen so the myocytes are able to produce more ATP whilst using less oxygen

26
Q

What is this switch in metabolism substrate known as?

A

FOETAL HEART METABOLISM

  • when pathological myocytes begin re-expressing foetal cardiac genes, they over-produce ANP, BNP and TGF-b
  • The altered gene expression also induces the production of protein isomers e.g isomers of metabolic enzymes and isomers of sarcomeric proteins
  • This all results in an ALTERED FUNCTIONALITY of the heart and it goes back to behaving as if it were foetal
27
Q

What are the mechanisms involved in pathological hypertrophy?

A
  1. Hypertrophic stimulus - stretch or neurohormonal signals such as Ang II or NA are released as a consequence
  2. Activation of stretch or neurohormonal receptor
  3. Intracellular signalling pathways are activated
  4. Pathways result in a change to gene expression causes the myocyte to begin expressing foetal genes
  5. Altered gene expression causes altered protein synthesis
  6. Altered protein synthesis results in HYPERTROPHY
28
Q

What is one of the initial steps involved in cardiac hypertrophy?

A

RECEPTOR ACTIVATION is one if the initial steps in triggering the myocardial response to stress stimuli

29
Q

What type of receptors are known to play an important role in both initiation and regulation of cardiac hypertrophy?

A

G-protein Coupled Receptors

30
Q

What does activation of G-protein coupled receptors in response to stress stimuli do?

A

Activation of G-protein coupled receptors is known to trigger intra-cellular transduction pathways that bring about hypertrophic response

31
Q

What transcription factors are needed to alter gene expression to re-induce the foetal gene programme?

A

NFAT, GATA4 and MEF2

32
Q

What signalling pathways are able to modifiy the transcription factors that activate foetal gene programme?

A

Mitogen-Activated Protein Kinases (MAP kinases) and Calcineurin

33
Q

What is fibrosis?

A

It is deemed the excessive deposition of extracellular matrix proteins such as Collagen

34
Q

Why is excess collagen deposited following cardiac injury or stress?

A

It is an adaptive response by the heart in an attempt to normalise wall stress and preserve cardiac output
-Depositing collagen is an attempt to increase the tensile wall strength of the myocardium and protect it from rupture

35
Q

What two types of fibrosis are there?

A
  1. Reparative Fibrosis-seen following MI

2. Reactive Fibrosis-in response to stress such as hypertension

36
Q

What is bad about fibrosis if it is just repairing damage?

A

Excess collagen is STIFF
Enhanced stiffness of the heart impedes contraction and relaxtion which causes distorted architecture and function
-Fibrosis also disturbs the conduction of action potentials so arrhythmias can occur

37
Q

What is the process of initiating fibrosis?

A
  1. Stimulus e.g stress such as hypertension or cardiac injury such as MI
  2. Fibroblasts are activated-usually by inflammatory cytokines released in response to the stimulus
  3. Fibroblasts proliferate and differentiate
  4. Fibroblasts produce more cytokines such as TGF-b and IL-6 to recruit more fibroblasts
  5. Once differentiated fibroblasts become ‘Myofibroblasts’
  6. Myofibroblasts produce ECM and types 1 and III collagen-FIBROSIS
  7. Myofibroblasts have contractile properties and so contract to reduce the area of damage
38
Q

Why is apoptosis needed in cardiac remodelling?

A

To rid the myocardium of cells beyond repair e.g ischaemic cells in MI

39
Q

What are the steps involved in Apoptosis?

A
  1. Cells that are damaged or stressed are triggered by the body to undergo apoptosis
  2. Cells begin to shrink and form BLEBS-proteases within the cell are activated to breakdown cellular components
  3. Proteases breakdown the nucleus which emits signals to attract macrophages
  4. The cell breaks in to smaller segments containing the cell components and destroyed nucleus
  5. Once in smaller pieces, macrophages can engulf and digest the cells
40
Q

What is proposed to contribute to progressive cardiac dysfunction in heart failure?

A

Excessive apoptosis and excessive loss of myocytes is proposed to contribute to progressive cardiac dysfunction

41
Q

What do samples of failing hearts in transplants show?

A

Samples taken from failing hearts during transplantation show that failing hearts have a 200-fold increase in the extent of apoptosis

42
Q

What are the two different pathways involved in apoptosis?

A
  1. Extrinsic Pathway

2. Intrinsic Pathway

43
Q

What is the extrinsic pathway of apoptosis?

A

Extracellular signals such as FAS (fatty acid synthase) and TNF (tumour necrosis factor) bind to cell receptors on cells the body wishes to get rid of and these are LETHAL LIGANDS that trigger the cells to undergo apoptosis

  • Binding of lethal ligands produces a DISC (Death initiating Signal Complex)
  • DISCs cause the release of Procaspase 8 which begins a torrent of cascades that forms CASPASE-the enzyme needed to trigger Apopotosis
44
Q

What is the intrinsic pathway of apoptosis?

A

The intrinsic pathway is activated following DNA damage or oxidative stress

  • DNA damage or oxidative stress releases Bax, BCL-2 and Tbid which bind to the mitochondria
  • Binding to the mitochondria causes release of Cytochrome C which results in the formation of an Apoptosome and activation of Caspase 9
  • Caspase 9 activate CASPASE cascades downstream which results in apoptosis
45
Q

What is an alternative mechanism of apoptosis?

A

Apoptosis-Inducing Factor can be released from the inner and outer membranes of Mitochondria in cell damage
-Apoptosis-Inducing factor causes the cell nucleus to condense its chromosomes and fragment its DNA to prepare for apoptosis

46
Q

What happens in Myocardial Injury such as an MI?

A
  1. The area is infiltrated by inflammatory cells as cell damage indicates something is wrong
  2. REACTION OF MONOCYTES/MACROPHAGES:
    - Release of Pro-fibrotic cytokines such as TGF-b causes stimulation of fibroblasts and deposition of collagen to increase tensile wall strength where damage has occured
    - Resulting in myocardial fibrosis
  3. REACTION OF NEUTROPHILS
    - Produce cytokines such as TNF and IL-6 which activates apoptosis to clear up damaged cells
    - but neutrophils also release Matrixmetalloproteases which degrade the Extracellularmatrix
    - This degradation of ECM contributes to myocardial wall thinning, but it also allows collagen fragments to alert that damage has occured which has a POTENT pro-inflammatory effect
47
Q

Overview of Physiological Remodelling:

A
  1. Normal or enhanced cardiac function
  2. NO fibrosis
  3. Normal gene expression (just enhanced protein synthesis)
  4. Proportional chamber enlargement
48
Q

Overview of Pathological Remodelling:

A
  1. Cardiac Dysfunction
  2. Fibrosis
  3. Re-induction of the Foetal Gene Programme
  4. Mycocyte necrosis and apoptosis
49
Q

Overview of Cardiac Failure:

A
  1. Advanced cardiac dysfunction
  2. Ventricular Dilation
  3. Extensive Fibrosis
  4. Myocyte Cell death
50
Q

How does cardiac remodelling following MI lead to heart failure?

A
  1. Infarction resulting in cell ischaemia
  2. Infact Extension-Necrosis and Apoptosis around the infarct area occurs (within hours)
  3. Infarct Wound Healing (within hours/days)
    - Inflammatory cell recruitment
    - Removal of necrotic tissue
    - Degradation of ECM
    - Angiogensis
    - Collagen deposition resulting in Scar formation-FIBROSIS
  4. Progressive Cardiac Remodelling
    - Scar formation by fibrosis
    - Myocyte Hypertrophy
    - reactive fibrosis
    - LV dilatation
    - Arrhythmias (fibrosis disrupts Action potential conduction)
    - Cardiac dysfunction due to restrictions of contraction and relaxation
    - Development of heart failure
51
Q

What is the injury phase of MI?

A
  1. Blockage of epicardial vessel
  2. Oxygen/nutrient starvation of the heart
  3. Myocyte necrosis
  4. Mycoyte death at the infarct border-INFARCT EXTENSION
52
Q

What happens in the acute inflammatory response following MI?

A
  1. Necrotic Myocytes release Danger Associated Molecular Patterns (danger signals called DAMPs)
  2. DAMPs cause cytokine and chemokine release
  3. Chemokines recruit monocytes which produce Monocytic Chemotactic Protein to recruit Macrophages to clear the nectrotic tissue
  4. Cytokines recruit neutrophils who release TNF and IL-6 to produce a pro-inflammatory environment and also MMPs to breakdown the ECM causing myocyte slippage
53
Q

What happens in early and late remodelling following MI?

A

In the region supplied by the infarcted artery, cardiomyocytes undergo massive cell death by apoptosis and necrosis

  • loss of myocytes and infarct expansion contribute to thinning of the ventricle wall and a decrease in the contractile function of the myocardium
  • Because the wall is thinner and blood continues to flow, the ventricle dilates
  • LV volume therefore increases and the non-infarcted myocardium is able to compensate by increasing inotropy
  • But this larger ventricular volume causes intensified wall stress so there is risk of wall rupture
  • To prevent rupture and normalise wall stress, scar tissue forms in the myocardium via the process of fibrosis
  • Myocyte hypertrophy as triggerd by mechanical stretch also contributes to normalising tensile wall strength
  • The RAAS and Sympathetic nervous system are both triggered into action following MI-related reduced cardiac output and this activation helps to compensate for reduced CO
54
Q

What happens in large infarcts?

A

there is usually progressive dilatation due to expansion of the infarct zone and a change in cardiac shape due to mixed myocyte hypertrophy
-Increased fibrosis and apoptosis also occurs

55
Q

What does a heart that has suffered a large infarct look like?

A

Enlarged and more spherical in shape with thin walls and poor contractile function

56
Q

What features lead to cardiac dysfunction?

A

Excessive collagen deposition by myofibroblasts in the non-infarcted zone contributes to myocyte apoptosis, stiffness of the myocardium, abnormalities in cardiac relaxation and contraction and disrupted action potential conduction

57
Q

What happens to cardiac output in cardiac dysfunction?

A

Cardiac output drops, as does blood pressure

58
Q

What triggers the RAAS system?

A

A reduction in renal blood flow

59
Q

What triggers the sympathetic nervous system?

A

lack of stimulation of the Baroreceptors

60
Q

How is the Sympathetic Nervous system triggered in cardiac dysfunction?

A

There is a fall in blood pressure so there is reduced carotid sinus firing and lack of baroceptor firing

  • Sensory afferent neurones from these receptors stimulate cardiovascular centres in the medulla
  • This stimulation decreases parasympathetic innervation and increases sympathetic
  • Increased sympathetic innervation causes bigger release of Noradrenaline and Adrenaline which activates adrenergic receptors to produce cAMP and triggers smooth muscle contraction resulting in vasoconstriction and boosted arterial resistance
  • Sympathetic innervation also activates b1-receptors which produces cAMP to increase inotropy and heart rate
61
Q

How is the RAAs system triggered in cardiac dysfunction?

A

Low cardiac output and low BP is triggered by the Juxtaglomerular apparatus in the kidneys (i.e reduced renal perfusion) and this triggers the release of Renin

  • Renin produces Angiotensin I which is then converted to Angiotensin II
  • Angiotensin II causes vasoconstriction and stimulates production of ADH
  • Angiotensin II then promotes production of Aldosterone which causes sodium and water retention to increase blood volume
  • But Ang II contributes to Fibrosis
62
Q

What are the long term effects of cardiac remodelling?

A

Chronic volume/pressure overload or neurohormonal stimulus results in pathological remodelling

  • Remodelling causes myocyte hypertrophy, apoptosis and intersitial fibrosis
  • This all contributes to reduced heart wall elasticity
  • Lack of elasticity further reduces the hearts ability to function due to restricted contraction and relaxation and the cycle starts again

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