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

Lecture 3 - Cardiac Remodelling Flashcards

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
Q

Stage 1 Intrinsic pathway till BAX activation in cytosol

A
  1. DNA lesion
  2. ATM activation ( serine threonine kinase)
  3. p53 activaton
  4. PUMA activation ( p53 unregulated modulator of apoptosis )
26
Q

Stage 2 intrinsic pathway till cytochrome C released in cytosol

A
  1. BAX activation in cytosol
  2. activated BAX becomes mitochondrial membrane bound
  3. opens channels in mitochondrial membrane
27
Q

Stage 3 intrinsic pathway

A
  1. Cytochrome C released in the cytosol
  2. Cyt C + APAF-1 form apoptosome
  3. apoptosome cleaves procaspase 9 to caspase 9
  4. caspase 9 cleaves procaspase 3 to caspase 3
28
Q

What does caspase 3 do?

A
  1. cleaves cytosolic and nuclear proteins

2. activates caspase activated DNase in the nucleus resulting in DNA fragmentation

29
Q

What are the two pathways in extrinsic pathway

A

FAS pathway and TNFR1

30
Q

What occurs in the FAS pathway?

A
  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
Q

What occurs in the TNFR1 pathway

A
  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
Q

Definition of fibrosis

A

excessive deposition of ECM proteins in particular collagen

33
Q

What is reactive fibrosis

A

deposition of ECM proteins following haemodynamic stress

34
Q

What is the aim of reactive fibrosis?

A

preserving cardiac output while normalizing wall stress

35
Q

Reparative fibrosis

A

occurs post-MI space made between dead myocytes so collagen deposition to connect remaining heart cells –> provides support

36
Q

What are the effects of fibrosis?

A 
enhanced cardiac stiffness
cardiac contraction affected
arrhythmias
cardiac dysfunction
heart failure
37
Q

Role of myocardial fibroblast in fibrosis?

A

increasing the production of collagen and other extracellular matrix proteins

38
Q

1.What are the stimuli for cardiac fibrogenesis

A

Ischemia / MI / oxidative stress / mechanical stretch / HTN/ hormones
MYOCYTE DEATH

39
Q
  1. What the stimulation of fibroblasts do?
A

proliferation and differentiation of fibroblasts

40
Q
  1. What do fibroblasts differentiate into?
A
  • ECM production
  • myofibroblasts
  • cytokine production
41
Q

What is the result of fibroblast differentiation

A

reactive and reparative fibrosis

42
Q

What happens after myocardial injury?

A

Infiltration by inflammatory cells

43
Q

What two cells are involved in the infiltration?

A

Neutrophils and monocytes

44
Q

What do neutrophils cause to be released

A

Cytokines (TNF-a) and MMPs

45
Q

What does the release of cytokines cause?

A

activation of apoptosis

46
Q

What does the release of MMPs cause?

A

degradation of collagen scaffold

47
Q

What do monocytes cause the release of?

A

pro-fibrotic cytokines(TGF-B)

48
Q

What do pro-fibrotic cytokines do?

A

stimulation of fibroblasts which causes myocardial fibrosis

49
Q

What occurs in myocardial infarction

A
  1. occlusion of epicardial vessel
  2. oxygen/nutrient starvation
  3. myocyte necrosis
  4. myocyte necrosis
  5. myocyte death at infarct border –> infarct extention
50
Q

What do the necrotic myocytes release?

A

DAMPs via TLRs

  • attracts neutrophils/monocytes to the site
  • leads to macrophages being present which clear necrotic tissue
51
Q

What contributes to Infarct expansion?

A

neutrophils releasing proteases which degrade existing ECM

52
Q

What does loss of myocytes and infarct expansion cause?

A

thinning of the ventricle wall and decrease in contractile function

53
Q

How does the heart adapt to intensified wall stress?

A

scar formation in the infarct zone and cardiomyocyte hypertrophy in the non-infarcted region

54
Q

What processes cause the adaption to intensitfied wall stress?

A
  1. Mechanical stretch
  2. neuro-hormonal activation
    - increased symapthetic outflow
    - RAAS activation
55
Q

What the late remodelling consequences of MI

A
  • Wall thinning
  • dilation of ventricle
  • spherical shape
  • contractile dysfunction
56
Q

What are the effects of reduced cardiac output?

A
  • Activation of SNS

- reduction in renal blood flow–> activation of RAAS

57
Q

how is the SNS activated by low CO?

A
  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
Q

how is the RAAS system activated

A

decrease in renal perfusion

59
Q

Describe how ATII becomes activated

A
  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
Q

What does AT-2 do?

A
  1. Increased sympathetic nerve activity
  2. Aldosterone secretion ( Na+ reabsorption + water retention )
  3. endothelin release ( vasoconstriction + increased BP)
  4. ADH –> water absorption
61
Q

What occurs as a result of AT-2 activation?

A
  • water + salt retention

- effective circulating volume increase

62
Q

What are the anti-remodelling therapies for heart failure

A
  1. Therapeutic interventions
    - ACEi / ARBs / MRA
    - reduce cell death/hypertrophy/fibrosis
  2. GLP-1 - effective in treating metabolic derangements
  3. Mechanical support –> ventricular assist device
    - limits ventricular dilation
  4. cell replacement of cardiomyocytes

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