Lecture 5: Heart Failure Mechanisms Flashcards
What is excitation-contraction coupling?
The spread of Ca within the myocyte during plateau phase of AP (excitation) and the Ca binding to troponin C resulting in contraction.
Describe Ca movement in the myocyte:
- 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
What regulates SERCA2a and its speed of action?
Phospholambam
What defines cardiac hypertrophy?
Cardiac ventricular dilation
Increased ventricular wall thickness
In general terms what can cause a change in cardiac structure?
A change in haemodynamic load can lead to a change in cardiac structure.
What are the types of haemodynamic loads?
Volume Overload
Pressure Overload
What is volume overload?
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.
What is pressure overload?
The aortic pressure increase (i.e hypertension) and the ventricle needs to develop higher pressures to open the aortic valve in systole.
Can pressure and volume overload occur at the same time?
Yes i.e an obese person with hypertension
Is the hypertrophic phenotype rigid?
No it is dynamic.
A increased ventricle thickness (pressure overload) can end up in a decompensated heart failure and ventricle dilation.
Its a continuum
What is the problem with increased ventricular wall thickness?
Increase in cardiomyocyte size is not necessarily accompanied by increased capillary density, therefore oxygen and nutrient supply may be limited.
What is the problem with volume overload?
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.
What results in hypertrophy?
The insult leads to a lot of signal changes that results in hypertrophy.
In hypertrophy what happens to gene expression?
- The heart reverts to a neonatal expression pattern called ‘fetal reprogramming’
What is expressed in fetal reprogramming / neonatal gene expression?
- Increased BNP (brain natriuretic peptide)
- Increased ANP (atrial natriuretic peptide)
- Switch from alpha to beta myosin heavy chain isoforms (MHC)
What are the causes of cardiac hypertrophy?
- Hypertension (pressure overload)
- Valve disease (pressure and volume overload)
- MI, regional dysfunction with volume overload.
What do insults on the heart cause?
Increased cardiac work leading to increased wall stress and cell stretch.
= Increased wall thickness or dilation
What is cardiac hypertrophy characterised by?
- Increased heart size and mass
- Increased protein synthesis
- Induction of neonatal genes/ fetal reprogramming
- Abnormal proteins
- Fibrosis (diseased cells die)
- Inadequate vasculature.
What does cardiac hypertrophy result in? (symptoms)
Cardiac dysfunction characterised by:
- Heart Failure (systolic/diastolic)
- Arrhythmias
- Neurohumoral stimulation
How can cardiac hypertension be modelled?
Transverse aortic constriction (pressure overload) in mouse.
What did TAC in mice show?
Found:
- Increased heart weight and size.
- Observed increase in cellular width.
What are some genetic causes of cardiac hypertrophy?
Familial dilated cardiomyopathy
Familial hypertrophic cardiomyopathy
What is familial dilated cardiomyopathy?
2-3 fold increase in heart size
- mutations in cytoskeletal proteins i.e titan (20%) or dystrophin
- Primary systolic impairment (spectrum of phenotypes)
What is familial hypertrophic cardiomyopathy?
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)
When does heart failure occur in cardiac hypertrophy?
Heart failure occurs in the advanced stages of the disease post compensation.
Why does heart failure occur?
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.
What are the types of heart failure?
Systolic failure (impaired contraction) or diastolic function (impaired relaxation) or both.
How can you measure cardiac function?
Echocardiography
How is systolic function measured in echocardiography?
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
What does echocardiography measure during systole?
Measures the differences of chamber size (distance between walls) over time to compare heart wall thickness.
What does echocardiography obtain from systolic measurements?
- Fractional shortening
- Ejection fraction (<40% in HF)
How is diastolic function measured in echocardiography?
Diastolic function can be assessed by looking at a longitudinal view of the heart (apical four chamber view)
What technique is applied during echocardiography for diastolic measurement?
Doppler flow (mitral valve) technique
What is the doppler flow technique and what does it measure?
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)
What does a change in blood velocity measured by the doppler technique indicate?
Change in velocity = change in pressure.
What is observed in diastolic function failure?
Impaired diastolic function the ration of E:A is reduced.
What are the types of heart failure?
Systolic heart failure
Diastolic heart failure
What is systolic heart failure?
Systolic heart failure: Impaired heart contraction
Heart Failure with Reduced Ejection Fraction
What is diastolic heart failure?
Diastolic heart failure: Impaired heart relaxation
Heart Failure with Preserved Ejection Fraction
What is the incidence of HFpEF?
- 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.
What are the risk factors of HFpEF?
- Age
- Gender
- Hypertension
- Diabetes
- Obesity
What are the risk factors for HFrEF?
- Coronary artery disease
- Family history of heart disease
- Hypertension
- Diabetes
- Obesity
What is the structural changes preemptive of HFrEF?
Enlarged ventricles = more blood
What is the structural change prior to HFpEF?
Stiff ventricles fill less blood than normal
What happens to the PV loop in diastolic dysfunction?
Ventricular compliance is reduced (increased ventricular stiffness) and LV volume is smaller.
PV-loop is smaller, and EDV is less.
How does fibrosis contribute to diastolic dysfunction?
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.
Is diastolic dysfunction associated correlated with extent of fibrosis?
Not necessarily.
What happens with diastolic dysfunction at the cellular level?
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.
What causes prolonged Ca levels in diastolic dysfunction and what does it cause?
The NCX and SERCA are slowed.
This results in prolonged Ca and this results in; delayed myofilament lengthening and cellular relaxation is impaired.
Describe the interplay of Ca and myocyte filaments;
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.
What promotes dissociation of Ca from TnC?
Phosphorylation of Tnl (i.e by b-adernergic signalling) promotes dissociation of Ca from TnC and myocyte relaxation.
How can myofilament Ca responsiveness be assessed?
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
At a cellular level what does diabetes affect?
Diabetes affects myofilament Ca
What is observered with regards to Ca levels in early diabetes?
An increase in myofilament Ca is evident early in disease progression. May underlie increased myocyte diastolic tone.
Describe myofilament sensitivity to Ca in early + late diabetes;
Pre-diabetic state;
- Increased myofilament Ca sensitivity
Advanced diabetic state
- Decreased myofilament Ca sensitivity.
What does late stage diabetes myofilament sensitivity translate to?
Diabetes = Diastolic dysfunction
Decreased Myofilament sensitivity leads to diastolic dysfunction
Whats the function of titan?
Protein maintains resting length of muscle during relaxation
- determines myocyte stiffness.
How does titan properties influence myocyte stiffness?
- Isoform switching phosphorylation and oxidation of titan can determine myocyte stiffness and contribute to impaired relaxation.
What are the biomarkers of heart damage?
- Acute myocardial infarction
- Plasma membrane of necrotic myocytes become leaky
- Molecules leak out of the cell into circulation
- (troponin 1, CK-MB myoglobin) these molecules can be used as biomarkers for diagnosis of MI
