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Cardiovascular Biology 311 > Lecture 5: Heart Failure Mechanisms > Flashcards

Lecture 5: Heart Failure Mechanisms Flashcards

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1
Q

What is excitation-contraction coupling?

A

The spread of Ca within the myocyte during plateau phase of AP (excitation) and the Ca binding to troponin C resulting in contraction.

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2
Q

Describe Ca movement in the myocyte:

A
  • Ca fluxes through the T tubule during Plateau due to the L-type Ca channels.
  • Ca passes through the DHPR channels in the t tubules and binds to the aligned RyR2 receptors on the SR
  • This is the Ca spark and there is Ca induced Ca release.
  • Ca binds to troponin C and this allows contraction to occur
  • Ca is removed from the cell my SERCA2A, Na/Ca (NCX) pump and CaATPase
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3
Q

What regulates SERCA2a and its speed of action?

A

Phospholambam

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4
Q

What defines cardiac hypertrophy?

A

Cardiac ventricular dilation

Increased ventricular wall thickness

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5
Q

In general terms what can cause a change in cardiac structure?

A

A change in haemodynamic load can lead to a change in cardiac structure.

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6
Q

What are the types of haemodynamic loads?

A

Volume Overload

Pressure Overload

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7
Q

What is volume overload?

A

The EDV is increased and the blood pushes on the ventricular walls causing increased pressure during diastole.

This leads to a change in cell signalling and thus a change in cell structure.

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8
Q

What is pressure overload?

A

The aortic pressure increase (i.e hypertension) and the ventricle needs to develop higher pressures to open the aortic valve in systole.

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9
Q

Can pressure and volume overload occur at the same time?

A

Yes i.e an obese person with hypertension

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10
Q

Is the hypertrophic phenotype rigid?

A

No it is dynamic.

A increased ventricle thickness (pressure overload) can end up in a decompensated heart failure and ventricle dilation.

Its a continuum

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11
Q

What is the problem with increased ventricular wall thickness?

A

Increase in cardiomyocyte size is not necessarily accompanied by increased capillary density, therefore oxygen and nutrient supply may be limited.

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12
Q

What is the problem with volume overload?

A

Volume overload is past the point of optimal ‘frank starling’ increase in force with myocyte stretch.

LaPlaces law describes the decrease in pressure with an increase in radius. Tension = p.r but tension limited.

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13
Q

What results in hypertrophy?

A

The insult leads to a lot of signal changes that results in hypertrophy.

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14
Q

In hypertrophy what happens to gene expression?

A
  • The heart reverts to a neonatal expression pattern called ‘fetal reprogramming’
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15
Q

What is expressed in fetal reprogramming / neonatal gene expression?

A
  • Increased BNP (brain natriuretic peptide)
  • Increased ANP (atrial natriuretic peptide)
  • Switch from alpha to beta myosin heavy chain isoforms (MHC)
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16
Q

What are the causes of cardiac hypertrophy?

A
  • Hypertension (pressure overload)
  • Valve disease (pressure and volume overload)
  • MI, regional dysfunction with volume overload.
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17
Q

What do insults on the heart cause?

A

Increased cardiac work leading to increased wall stress and cell stretch.

= Increased wall thickness or dilation

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18
Q

What is cardiac hypertrophy characterised by?

A
  • Increased heart size and mass
  • Increased protein synthesis
  • Induction of neonatal genes/ fetal reprogramming
  • Abnormal proteins
  • Fibrosis (diseased cells die)
  • Inadequate vasculature.
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19
Q

What does cardiac hypertrophy result in? (symptoms)

A

Cardiac dysfunction characterised by:

  • Heart Failure (systolic/diastolic)
  • Arrhythmias
  • Neurohumoral stimulation
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20
Q

How can cardiac hypertension be modelled?

A

Transverse aortic constriction (pressure overload) in mouse.

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21
Q

What did TAC in mice show?

A

Found:

  • Increased heart weight and size.
  • Observed increase in cellular width.
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22
Q

What are some genetic causes of cardiac hypertrophy?

A

Familial dilated cardiomyopathy

Familial hypertrophic cardiomyopathy

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23
Q

What is familial dilated cardiomyopathy?

A

2-3 fold increase in heart size

  • mutations in cytoskeletal proteins i.e titan (20%) or dystrophin
  • Primary systolic impairment (spectrum of phenotypes)
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24
Q

What is familial hypertrophic cardiomyopathy?

A

3-4 fold increase in heart size

  • 1 in 500 incidences
  • mutations in sarcomere proteins (troponin, beta-MHC, alpha-tropomyosin, myosin binding protein c)
  • Most common cause of sudden cardiac death in <35 year olds. (usually during or after exercise due to arrhythmias)
25
Q

When does heart failure occur in cardiac hypertrophy?

A

Heart failure occurs in the advanced stages of the disease post compensation.

26
Q

Why does heart failure occur?

A

Early adaptations (to cardiac insult) to preserve function (i.e hypertrophy) can become maladaptive and the heart function fails to meet the demands of the body.

27
Q

What are the types of heart failure?

A

Systolic failure (impaired contraction) or diastolic function (impaired relaxation) or both.

28
Q

How can you measure cardiac function?

A

Echocardiography

29
Q

How is systolic function measured in echocardiography?

A

Systolic function can be assessed by looking at the cross sectional view of the heart (parasternal axis)

Line up with papillary muscle (standard) for all patients

30
Q

What does echocardiography measure during systole?

A

Measures the differences of chamber size (distance between walls) over time to compare heart wall thickness.

31
Q

What does echocardiography obtain from systolic measurements?

A
  • Fractional shortening

- Ejection fraction (<40% in HF)

32
Q

How is diastolic function measured in echocardiography?

A

Diastolic function can be assessed by looking at a longitudinal view of the heart (apical four chamber view)

33
Q

What technique is applied during echocardiography for diastolic measurement?

A

Doppler flow (mitral valve) technique

34
Q

What is the doppler flow technique and what does it measure?

A

Measures blood flow velocity through mitral valve.

Forms two waves:

  • E wave: Larger, blood flowing into the ventricle by passive filling (due to pressure gradient)
  • A wave: Blood flowing from the atria into the ventricles by active filling (atrial contraction)
35
Q

What does a change in blood velocity measured by the doppler technique indicate?

A

Change in velocity = change in pressure.

36
Q

What is observed in diastolic function failure?

A

Impaired diastolic function the ration of E:A is reduced.

37
Q

What are the types of heart failure?

A

Systolic heart failure

Diastolic heart failure

38
Q

What is systolic heart failure?

A

Systolic heart failure: Impaired heart contraction

Heart Failure with Reduced Ejection Fraction

39
Q

What is diastolic heart failure?

A

Diastolic heart failure: Impaired heart relaxation

Heart Failure with Preserved Ejection Fraction

40
Q

What is the incidence of HFpEF?

A
  • Prevalence higher in women
  • 1 in 4 diabetics have HFpEF
  • Ageing correlates with increase HFpEF this is because we have an ageing population with rising diabetes.
41
Q

What are the risk factors of HFpEF?

A
  • Age
  • Gender
  • Hypertension
  • Diabetes
  • Obesity
42
Q

What are the risk factors for HFrEF?

A
  • Coronary artery disease
  • Family history of heart disease
  • Hypertension
  • Diabetes
  • Obesity
43
Q

What is the structural changes preemptive of HFrEF?

A

Enlarged ventricles = more blood

44
Q

What is the structural change prior to HFpEF?

A

Stiff ventricles fill less blood than normal

45
Q

What happens to the PV loop in diastolic dysfunction?

A

Ventricular compliance is reduced (increased ventricular stiffness) and LV volume is smaller.

PV-loop is smaller, and EDV is less.

46
Q

How does fibrosis contribute to diastolic dysfunction?

A

Increased cell death in heart failure;

  • Collagen forms b/w myocytes = interstitial fibrosis
  • Fibroblasts activated
  • affects compliance and electrical conduction
  • increased risk of cardiac dysfunction and arrhythmias.
47
Q

Is diastolic dysfunction associated correlated with extent of fibrosis?

A

Not necessarily.

48
Q

What happens with diastolic dysfunction at the cellular level?

A

It affects excitation contraction coupling by;

  • Myocyte relaxation occurs when cytostolic Ca is pumped back to the SR by SERCA and extruded from the cell via NCX + CaATPase

but in diastolic dysfunction there is prolonged Ca levels.

49
Q

What causes prolonged Ca levels in diastolic dysfunction and what does it cause?

A

The NCX and SERCA are slowed.

This results in prolonged Ca and this results in; delayed myofilament lengthening and cellular relaxation is impaired.

50
Q

Describe the interplay of Ca and myocyte filaments;

A

1) Ca binds to troponin c (TnC)
2) TnC changes conformation
3) Tnl moves away from the actin-myosin dining site.
4) Actin binds to myosin and contraction occurs
5) As (Ca)i falls, Ca dissociates from TnC
6) Tnl again blocks the actin-myosin binding site
7) Relaxation occurs.

51
Q

What promotes dissociation of Ca from TnC?

A

Phosphorylation of Tnl (i.e by b-adernergic signalling) promotes dissociation of Ca from TnC and myocyte relaxation.

52
Q

How can myofilament Ca responsiveness be assessed?

A

Monitoring cardiomyocyte shortening simultaneously with Ca

  • Determine whether Ca required for contraction is different.
  • Timecourse of relaxation is slow enough to monitor the fluorescence of Ca and is in equilibrium with cellular shortening.
  • This phase can be used to determine the level of myocyte tone for a given level of Ca
53
Q

At a cellular level what does diabetes affect?

A

Diabetes affects myofilament Ca

54
Q

What is observered with regards to Ca levels in early diabetes?

A

An increase in myofilament Ca is evident early in disease progression. May underlie increased myocyte diastolic tone.

55
Q

Describe myofilament sensitivity to Ca in early + late diabetes;

A

Pre-diabetic state;
- Increased myofilament Ca sensitivity
Advanced diabetic state
- Decreased myofilament Ca sensitivity.

56
Q

What does late stage diabetes myofilament sensitivity translate to?

A

Diabetes = Diastolic dysfunction

Decreased Myofilament sensitivity leads to diastolic dysfunction

57
Q

Whats the function of titan?

A

Protein maintains resting length of muscle during relaxation

  • determines myocyte stiffness.
58
Q

How does titan properties influence myocyte stiffness?

A
  • Isoform switching phosphorylation and oxidation of titan can determine myocyte stiffness and contribute to impaired relaxation.
59
Q

What are the biomarkers of heart damage?

A
  1. Acute myocardial infarction
  2. Plasma membrane of necrotic myocytes become leaky
  3. Molecules leak out of the cell into circulation
  4. (troponin 1, CK-MB myoglobin) these molecules can be used as biomarkers for diagnosis of MI

Cardiovascular Biology 311 (18 decks)

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