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Pumps Pipes and Electrics > Lecture 3 - Cardiac Remodelling > Flashcards

Lecture 3 - Cardiac Remodelling Flashcards

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1
Q

what are the major contributors to cardiac remodelling

A
  1. Myocytes
  2. Interstitium
  3. Fibroblasts
  4. Inflammatory cells
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2
Q

What is physiological remodelling

A

compensatory change in structure and function of heart in response to exercise / pregnancy

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3
Q

What is pathological remodelling

A

Changes that occur due to underlying disease. Begins as compensation and progresses to maladaptive
- HTN /heart valve disease /Post-MI/cardiomyopathy

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4
Q

Processes in cardiac remodelling

A
  1. Hypertrophy
  2. Apoptosis
  3. Fibrosis
  4. Inflammation
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5
Q

Explain eccentric hypertrophy

A

-volume overload–> physiologically ( endurance athletes ) / pathologically (valve disease )
Thin wall + large chamber size
Serial organization of sacromeres

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6
Q

Explain concentric hypertrophy

A

Pressure overload –> physiologically ( strength training) / pathologically ( HTN/aortic stenosis)
Thick wall + small chamber size
parallel organization of sarcomeres

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7
Q

Why does concentric remodelling occur post MI

A

maintain adequate cardiac output and counteract infarct expansion

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8
Q

What can infarct expansion lead to

A

eccentric hypertrophy and heart failure

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9
Q

What is different between physiological and pathological hypertrophy

A

In pathologoical hypertrophy there is:

fibrosis / apoptosis / inflammation/ fetal gene reactivation / irreversible/ increased glucose metabolism

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10
Q

What happens to metabolism in pathological hypertrophy

A

fatty acid oxidation to glucose metabolism

allows the heart to produce more ATP per molecule oxygen

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11
Q

Fetal gene program

A

response of the heart to haemodynamic / metabolic stress

-preference of glucose over fatty acids

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12
Q

Pathological pathway:

Initiating stimulus

A

Cardiomyopathy / disease

  • activation of ATII / ET-1 / NE
  • Bind to GPCR receptor on cell membrane
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13
Q

Pathological pathway:

Signalling pathways

A

GPCR activation leads to the release of GaQ

- this leads to the release of MAPKs / calmodulin / protein kinases C / calcineurin

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14
Q

Pathological pathway:

Cellular responses

A
  • protein synthesis
  • increased cell size
  • gene expression
  • fetal gene expression
  • cardiac fibrosis
  • cell death
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15
Q

Pathological pathway:

Cardiac function

A

depressed

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16
Q

Physiological growth:

stimulus

A

postnatal growth / excercise / pregnancy

  • Growth factors –>IGF-1
  • bind to RTK receptors
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17
Q

Physiological growth:

signalling pathways

A

RTK receptor activation
causes the release of PI3K (p110a)
-leads to the activation of Akt

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18
Q

Physiological growth:

Cellular responses

A

Gene expression
protein synthesis
increase in cell size

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19
Q

What is apoptosis

A

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

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20
Q

What does apoptosis do in the myocardium

A

increased apoptosis in myocytes contributes to progressive cardiac dysfunction in heart failure

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21
Q

Process of apoptosis

A
  1. cell damage triggers apoptosis
  2. cell shrinks / membrane remodelling/ chromatin condensation
  3. DNA fragmentation / membrane budding / signals emitted to attract macrophages
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22
Q

What are the two pathways in apoptosis

A 
Intrinsic pathway ( mitochrondrial)
Extrinsic ( death receptor pathway)
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23
Q

What is the extrinsic pathway induced by?

A
  • extracellular signals –> ligands binding to specific receptors
  • Fas receptors / TNFR1
  • DISC complex is formed and caspase 8 activated
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24
Q

what is the intrinsic pathway induced by?

A
  • DNA damaged /oxidative stress

- the mitochrondria releases cyt c which leads to the formation of the apoptosome and activation of caspase 9

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25
Stage 1 Intrinsic pathway till BAX activation in cytosol
1. DNA lesion 2. ATM activation ( serine threonine kinase) 3. p53 activaton 4. PUMA activation ( p53 unregulated modulator of apoptosis )
26
Stage 2 intrinsic pathway till cytochrome C released in cytosol
5. BAX activation in cytosol 6. activated BAX becomes mitochondrial membrane bound 7. opens channels in mitochondrial membrane
27
Stage 3 intrinsic pathway
8. Cytochrome C released in the cytosol 9. Cyt C + APAF-1 form apoptosome 10. apoptosome cleaves procaspase 9 to caspase 9 11. caspase 9 cleaves procaspase 3 to caspase 3
28
What does caspase 3 do?
1. cleaves cytosolic and nuclear proteins | 2. activates caspase activated DNase in the nucleus resulting in DNA fragmentation
29
What are the two pathways in extrinsic pathway
FAS pathway and TNFR1
30
What occurs in the FAS pathway?
1. FasL receptors on cytotoxic T cell bind to FasR receptors 2. This leads to the formation of DISC 3. formation of DISC allows procaspase 8 to activate caspase 8 which activates caspase 3
31
What occurs in the TNFR1 pathway
1. TNFa binds to TNFR1 receptor 2. conformational change of receptors 3. dissociation of SODD from receptor 4. recruitment of TRADD + FADD 5. cleavage of procaspase 8 to caspase 8 6. clevage of procaspase 3 to caspase 3
32
Definition of fibrosis
excessive deposition of ECM proteins in particular collagen
33
What is reactive fibrosis
deposition of ECM proteins following haemodynamic stress
34
What is the aim of reactive fibrosis?
preserving cardiac output while normalizing wall stress
35
Reparative fibrosis
occurs post-MI space made between dead myocytes so collagen deposition to connect remaining heart cells --> provides support
36
What are the effects of fibrosis?
``` enhanced cardiac stiffness cardiac contraction affected arrhythmias cardiac dysfunction heart failure ```
37
Role of myocardial fibroblast in fibrosis?
increasing the production of collagen and other extracellular matrix proteins
38
1.What are the stimuli for cardiac fibrogenesis
Ischemia / MI / oxidative stress / mechanical stretch / HTN/ hormones MYOCYTE DEATH
39
2. What the stimulation of fibroblasts do?
proliferation and differentiation of fibroblasts
40
3. What do fibroblasts differentiate into?
- ECM production - myofibroblasts - cytokine production
41
What is the result of fibroblast differentiation
reactive and reparative fibrosis
42
What happens after myocardial injury?
Infiltration by inflammatory cells
43
What two cells are involved in the infiltration?
Neutrophils and monocytes
44
What do neutrophils cause to be released
Cytokines (TNF-a) and MMPs
45
What does the release of cytokines cause?
activation of apoptosis
46
What does the release of MMPs cause?
degradation of collagen scaffold
47
What do monocytes cause the release of?
pro-fibrotic cytokines(TGF-B)
48
What do pro-fibrotic cytokines do?
stimulation of fibroblasts which causes myocardial fibrosis
49
What occurs in myocardial infarction
1. occlusion of epicardial vessel 2. oxygen/nutrient starvation 3. myocyte necrosis 4. myocyte necrosis 5. myocyte death at infarct border --> infarct extention
50
What do the necrotic myocytes release?
DAMPs via TLRs - attracts neutrophils/monocytes to the site - leads to macrophages being present which clear necrotic tissue
51
What contributes to Infarct expansion?
neutrophils releasing proteases which degrade existing ECM
52
What does loss of myocytes and infarct expansion cause?
thinning of the ventricle wall and decrease in contractile function
53
How does the heart adapt to intensified wall stress?
scar formation in the infarct zone and cardiomyocyte hypertrophy in the non-infarcted region
54
What processes cause the adaption to intensitfied wall stress?
1. Mechanical stretch 2. neuro-hormonal activation - increased symapthetic outflow - RAAS activation
55
What the late remodelling consequences of MI
- Wall thinning - dilation of ventricle - spherical shape - contractile dysfunction
56
What are the effects of reduced cardiac output?
- Activation of SNS | - reduction in renal blood flow--> activation of RAAS
57
how is the SNS activated by low CO?
1. Low CO 2. Fall in BP 3. decreased firing of cartoid sinus + baroreceptors 4. increased sympathetic out / reduced parasympathetic 5. vasoconstriction/increased force of contraction/increased HR/increased BP 6. further myocardial remodelling
58
how is the RAAS system activated
decrease in renal perfusion
59
Describe how ATII becomes activated
1. Renin cleaves angiotensinogen produced by the liver to AT-1 2. AT-1 is cleaved by ACE which is present in the lungs 3. AT-2 formed
60
What does AT-2 do?
1. Increased sympathetic nerve activity 2. Aldosterone secretion ( Na+ reabsorption + water retention ) 3. endothelin release ( vasoconstriction + increased BP) 4. ADH --> water absorption
61
What occurs as a result of AT-2 activation?
- water + salt retention | - effective circulating volume increase
62
What are the anti-remodelling therapies for heart failure
1. Therapeutic interventions - ACEi / ARBs / MRA - reduce cell death/hypertrophy/fibrosis 2. GLP-1 - effective in treating metabolic derangements 4. Mechanical support --> ventricular assist device - limits ventricular dilation 5. cell replacement of cardiomyocytes

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