CVS Flashcards
1
Q
What is needed for contraction of a single ventricular cell?
A
Extracellular calcium
2
Q
What is the approximate size of a ventricular myocyte and T tubules?
A
100 micrometres
3
Q
Describe the excitation-contraction coupling of the heart including the receptors involved.
A
Depolarisation causes the opening of L-type calcium channels. This leads to influx of calcium into the myocyte. The calcium then binds to the Ryanodine receptor and leads to the release of calcium from the sarcoplasmic reticulum. SERCA then takes the calcium from the cytoplasm back into the SR. The Na/Ca exchanger pumps out as much calcium as entered the cell in the first place.
4
Q
What is the shape of the force-calcium relationship?
A
SIGMOIDAL
5
Q
What concentration of calcium is sufficient to generate maximum contraction?
A
10 micromolar
6
Q
Compare the length-tension relationship in skeletal and cardiac muscle.
A
Cardiac muscle is much more resistant to stretch. Cardiac muscle exerts a lot more passive force.
7
Q
What are the two types of contraction used by the heart?
A
Isometric and Isotonic
8
Q
What is Preload?
A
The weight that stretches the muscle before it is stimulated to contract
9
Q
What is Afterload?
A
The weight that is not apparent to the muscle in the resting state and is only encountered once the muscle has started to contract
10
Q
What is the effect of increasing preload?
A
Increasing preload increases the force exerted by the muscle fibres
11
Q
What are the effects of increasing afterload?
A
Increasing afterload decreases the amount of shortening of muscle fibres and decreases the velocity of shortening of the fibres.
12
Q
What are the in vivo correlates of preload?
A
End diastolic volume (this is the venous return to the heart that stretches the muscle fibres)
13
Q
What are the in vivo correlates of afterload?
A
Blood pressure in the vessels leaving the ventricles.
14
Q
What is a simple measure of afterload?
A
Diastolic arterial blood pressure
15
Q
State Starling’s Law.
A
Increase in diastolic fibre length increases ventricular contraction.
16
Q
Starling’s law is caused by what two factors?
A
Changes in the number of myofilament cross-bridges
Changes in the calcium sensitivity of the myofilaments
17
Q
State two possible explanations for increasing calcium sensitivity of the myofilaments.
A
When the muscles are stretched, the lattice spacing (spacing between filaments) decreases meaning that for the same amount of calcium, more cross bridges can be formed.
When sarcomere length changes, there is a conformational change in troponin C that gives it a higher affinity for calcium.
18
Q
What is Stroke Work?
A
Work done by the heart to eject blood under pressure into the aorta and pulmonary artery.
19
Q
State the equation for stroke work.
A
Stroke Work = Stroke Volume x Pressure (at which the blood is ejected)
Stroke volume is greatly affected by preload, afterload and contractility.
20
Q
State the law of Laplace.
A
When the pressure within a cylinder is kept constant, tension increases with increasing radius. T = PR.
21
Q
What is the physiological relevance of the law of Laplace with regards to the structure of the right and left ventricles?
A
The left ventricle has a smaller radius of curvature than the right ventricle meaning that the left ventricle is able to generate higher pressures with similar wall tension.
22
Q
What is the clinical significance of the law of Laplace?
A
In dilated cardiomyopathy, the radius of curvature increases and hence the pressure generated decreases.
23
Q
State the different phases of the cardiac cycle in order.
A
Atrial Systole Isovolumic Contraction Rapid Ejection Reduced Ejection Isovolumic Relaxation Rapid Ventricular Filling Reduced Ventricular Filling
24
Q
What is the Ejection Fraction?
A
SV/EDV - the proportion of the blood in the heart that is pumped out in one contraction
25
What ECG change is seen in atrial systole?
P wave - atrial depolarisation
26
What abnormal heart sound could be heard during atrial systole and what could it be a result of?
S4 - this could be due to tricuspid incompetence, pulmonary embolism or congestive heart failure
27
How does atrial pressure change during atrial contraction?
Atrial pressure shows a small increase - a wave
28
Describe the pressure and volume changes that take place during isovolumic contraction.
The valves are all closed so there is no change in volume but the pressure increases dramatically.
29
What heart sound will be heard during isovolumic contraction?
S1 - closing of the atrioventricular valves
30
What ECG change is seen during isovolumic contraction?
QRS complex - ventricular depolarisation
31
Describe what happens during rapid ejection.
The ventricular pressure exceeds the aortic and pulmonary pressures so the aortic and pulmonary valves open and blood rapidly flows out into the aorta and pulmonary artery.
32
What causes the 'c wave' in atrial pressure during rapid ejection?
The ventricles contracting pushes the tricuspid valve inwards causing a slight increase in atrial pressure - c wave
33
Describe the electrical activity and heart sound heard during rapid ejection.
There is no electrical activity - isoelectric line on ECG. No heart sounds are heard.
34
Describe what happens during reduced ejection.
Marks the end of systole. Ventricular pressure begins to fall
T wave on the ECG due to the repolarisation of the ventricles. There are NO heart sounds because none of the valves are shutting.
35
What is the dichrotic notch and when does it occur?
The dichrotic notch is caused by the elastic recoil of the aorta causing a small rise in aortic pressure once ventricular contraction has ended.
36
What changes in pressure occur during isovolumic relaxation?
The atrial pressure increases due to the filling against closed valves - v wave. Volume of the ventricles does not change.
37
What heart sound can be heard during isovolumic relaxation?
S2 - this is due to the shutting of the aortic and pulmonary valves
38
What changes in volume and pressure take place during rapid ventricular filling?
There is a gradual increase in ventricular volume but ventricular pressure remains about the same. Atrial pressure decreases.
39
What abnormal heart sound can be heard during rapid ventricular filling and what could it be a result of?
S3 - can be due to mitral incompetence or severe hypertension
40
What happens during reduced ventricular filling?
Ventricular volume increases more slowly. This is also called diastasis. There are NO changes on ECG and NO heart sounds.
41
Which graph is commonly used to illustrate cardiac physiology?
Wiggers diagram
42
What is the difference between the pressures in the pulmonary circulation and in the systemic circulation?
The pressures in the pulmonary circulation are much lower (though the patterns of pressure changes are the same)
43
State the average pressures of the systemic circulation and of the pulmonary circulation.
Systemic - 120/80
| Pulmonary - 25/5
44
What is used to measure preload on the left side of the heart?
PAWP - Pulmonary Artery Wedge Pressure
| By measuring the pulmonary artery pressure you get an indirect measurement of the left atrial pressure
45
What do points 1-4 on the pressure-volume loop indicate?
```
1 = End diastolic volume
2 = Isovolumic contraction (pressure has increased but volume hasn't)
3 = End systolic volume
4 = Isovolumic relaxation (volume doesn't change but pressure has decreased)
```
46
Which feature of the pressure-volume loop indicates stroke volume?
Distance between point 2 and point 3
47
Which points on the pressure-volume loop indicate preload and afterload?
```
Preload = point 1 (because it indicates the venous return to the heart and hence the stretch on the ventricular muscle)
Afterload = point 2 (this is the end of isovolumic contraction when the pressure in the aorta and pulmonary artery (the afterload) is first experienced)
```
48
Draw a diagram of the frank-starling relationship combined with a pressure-volume loop.
Starling's Law = increased muscle fibres length causes increased ventricular contraction
The graph should be force against muscle fibre length (and pressure against volume)
49
How does the pressure-volume loop change if the venous return to the heart is increased?
Points 1 and 2 move further to the right so the distance between 2 and 3 and hence the stroke volume, increases
50
How does the pressure-volume loop change if the afterload is increased?
Points 3 and 4 move further to the right so the distance between 2 and 3, and hence the stroke volume, decreases. Also, point 2 and 3 move in a positive y direction so more pressure is required to open the aortic and pulmonary valves.
51
What three factors can affect cardiac output?
Preload
Afterload
Contractility
52
What is a simple measure of cardiac contractility?
Ejection Fraction
53
How does the Frank-Starling Relationship change with increased contractility?
The gradient of the ESV line changes
54
How does the pressure-volume loop change during exercise?
It becomes wider and the points move further out in all directions. EDV increases and ESV decreases (hence ejection fraction increases)
55
Explain the potassium hypothesis.
If a membrane is permeable to potassium and there is a higher concentration on one side of the membrane, the potassium will move down the concentration gradient and it will carry positive charge with it. As it carries positive charge with it, one side of the membrane will have a more positive charge than the other. This would mean that the electrochemical gradient opposes the concentration gradient. Eventually the electrochemical gradient will equal the concentration gradient that there would be no net movement of potassium. The cell membrane is more permeable to potassium ions than anything else, which is why the membrane potential is close to the equilibrium potential of potassium.
56
What are the intracellular and extracellular concentrations of potassium ions?
```
Inside = 120 mM
Outside = 5 mM
```
57
value does the Nernst equation give when using potassium concentrations and what is its significance?
-80 mV - very close to the actual resting membrane potential of a ventricular myocyte hence meaning that potassium is the main determinant in the resting membrane potential
58
What value does the Nernst equation give when using sodium concentration and what is its significance?
+66mV - during the upstroke of an action potential, when the membrane is most permeable to sodium, the membrane potential will reach around +66 mV
59
What is the duration of an action potential in a nerve compared to a ventricular myocyte?
In a nerve = 2 ms
| Ventricular myocyte = 200-400 ms
60
Describe and explain the cardiac action potential.
The cardiac action potential has a normal upstroke due to opening of sodium channels. Then there is a small repolarisation caused by transient outward potassium current. The membrane potential then plateaus for a long time due to the activation of long acting L-type calcium channels. Influx of calcium balances the efflux of potassium for a long while and hence maintains a constant membrane potential. Eventually, the membrane repolarises due to the inactivation of the L-type calcium channels.
61
What is the difference between absolute refractory period and relative refractory period?
During the absolute refractory period, the sodium channels cannot be reopened - this means that regardless of the stimulus strength, an action potential cannot be generated.
During the relative refractory period, an action potential can be generated, but only if there is a stimulus of greater than normal strength.
62
What is full recovery time?
The time at which a normal action potential can be elicited by a stimulus of normal strength.
63
What is the key difference between skeletal muscle and cardiac muscle in terms of excitation and tetanus?
With skeletal muscle, repolarisation occurs very early in the process of contraction. So the muscle can be re-stimulated very soon after the first action potential causing summation and tetany. The long absolute refractory period of cardiac muscle means that by the time the action potential has finished, the muscle is well into the process of contraction and hence action potentials can't be generated at a high enough frequency for them to summate and cause tetany.
64
What causes the early repolarisation in the cardiac action potential?
Transient outward potassium current
65
What causes the plateau in the cardiac action potential?
The opening of L-type calcium channels allows calcium influx, which just about balances the efflux of potassium so the membrane potential remains around 0 mV
66
State three drugs used in anti-hypertensive care and their targets.
Nifedipine
Nitrendipine
Nisoldipine
These are all calcium channel antagonists
67
Describe the changes in ion channels that takes place during repolarisation.
The normal potassium channels open slowly starting repolarisation.
Then a weird potassium current (IK1) starts that is large and flows through diastole. This repolarises the membrane and helps to maintain resting membrane potential and reduce the risk of arrhythmia.
68
Different cells within the heart have different action potential shapes. What causes this difference?
Differences in the expression of ion channels
69
Why don't sinoatrial nodal cells have a stable resting membrane potential?
They don't have any IK1 potassium channels so they can't maintain a stable resting membrane potential.
70
What causes the upstroke in the action potential of sinoatrial nodal cell action potentials?
The upstroke is caused by calcium influx (there is very little sodium movement involved)
71
How does the autonomic nervous system control heart rate?
It alters the gradient of the pacemaker potential thus making it quicker or slower to reach threshold potential and generate an action potential.
72
Where are purkinje fibres found?
They run beneath the endocardium and penetrate about 1/3 of the way into the myocardium
73
What feature provides low resistance pathways between cells for impulse propagation?
Gap junctions
74
What equation connects blood flow, pressure difference and resistance?
Flow = pressure difference/resistance
75
What factors affect vascular resistance?
Vessel radius, vessel length, blood viscosity
76
What is the relationship between vascular resistance and blood vessel radius?
Poiseuille's law: resistance is inversely proportional to r^4
77
What are the major resistance vessels in the body?
Arterioles
78
Why can change in blood pressure be substituted by MAP?
The arterial blood pressure is usually MAP and the blood pressure in the veins is usually around 0 mm Hg so the change in blood pressure through a capillary bed is usually around MAP.
79
What is the normal state of vascular smooth muscle?
They are normally in a state of partial vascular constriction - vascular tone
80
What are the two controls of vessel radius?
Intrinsic controls with the aim of changing perfusion to match metabolic needs
Extrinsic controls with the aim of regulating arterial blood pressure
81
Describe how vessel radius responds to the chemical environment.
When tissues are highly metabolically active they will produce a lot of ATP and use up a lot of oxygen. The increase uptake of oxygen is detected by the tissues, which sends a message to the arteriolar smooth muscle to dilate. This is active hyperemia.
82
Describe how vessel radius responds to the physical environment.
When there is a decrease in blood temperature, the vascular smooth muscle will constrict so that less blood reaches the surface and so less heat is radiated away.
83
How can the flow rate, pressure difference and resistance equation be applied to the entire circulation?
Flow rate is cardiac output, pressure difference is mean arterial blood pressure and resistance is total peripheral resistance. CO = MABP/TPR
84
What are the two pathways controlling arterial blood pressure?
Neural and Hormonal Pathways
85
Where is the centre that regulates arterial blood pressure found?
In the medulla - cardiovascular control centre
86
Describe the neuronal control of arterial blood pressure.
The brain controls arterial blood pressure via ADRENORECEPTORS:
o Alpha - CONSTRICTION
o Beta - Dilation
The sympathetic nervous system can also increase production of catecholamines (noradrenaline and adrenaline) from the adrenal medulla, which binds to increase heart rate and blood pressure
87
Describe the hormonal control of arterial blood pressure.
Main hormones involved in blood pressure:
o Angiotensin II
o Vasopressin
These are both potent vasoconstrictors
88
What is capillary exchange?
Delivery of metabolic substrates to the cells of an organism
89
What tissues have a high capillary density?
Skeletal muscle, myocardium, brain, lungs
90
What are the three main types of capillary and how do they differ?
CONTINUOUS - small water filled gap junctions that allow the passage of electrolytes and small molecules (most substances move through endothelial cells) - MOST COMMON
FENESTRATED - slightly bigger gaps allowing slightly larger molecules to pass through
DISCONTINUOUS - large holes in the capillary
91
What is the most common type of capillary?
Continuous
92
How is the blood brain barrier different to other capillaries?
You do NOT have water-filled gap junctions but instead you have TIGHT gap junctions. So access of substances to the brain is tightly regulated.
93
What is the name given to hydrostatic pressure and plasma osmotic pressure?
Starling's Forces
94
Describe some characteristics of the lymphatic system.
Consists of blind-ended lymphatic capillaries
Valves - prevent backflow
All but the right upper quadrant of the body drains via the thoracic duct into the left subclavian vein
The right upper quadrant drains into the left subclavian vein
95
What are the three layers of blood vessels?
Tunica intima - mainly vascular endothelium
Tunica media - mainly smooth muscle
Tunica adventitia - external layer containing blood vessels, collagen, elastin
96
How do blood vessels regulate its own blood pressure?
Blood vessels regulate their own pressure depending on how much blood is flowing past it (SHEAR STRESS).
Mechanoreceptors on the endothelial cells detect an increased blood flow and secrete vasodilators to bring the blood flow down.
97
What are the two main vasodilatory molecules? What other effect do they have?
Nitric Oxide
Prostacyclin
Inhibit the aggregation of platelets
98
What are the three main vasoconstricting molecules?
Thromboxane A2
Endothelin-1
Angiotensin II
99
What is special about endothelin-1?
Endothelin-1 can cause BOTH vasoconstriction AND vasodilation - it has different receptors on different tissues
100
Describe the synthesis of nitric oxide.
A substrate that triggers NO production will bind to a Gq protein linked receptor and activate PLC.
PIP2 ----> IP3 + DAG
IP3 ----> increase intracellular [Ca2+] (release from SR)
Increased [Ca2+] ---> activate endothelial nitric oxide synthase
Nitric Oxide Synthase catalyses:
L-arginine + Oxygen ---> L-citrulline + NO
101
Describe the action of nitric oxide.
Nitric Oxide binds to receptors on smooth muscle cells and activates GUANYLYL CYCLASE ---> increase in cGMP ---> activation of Protein Kinase G ---> RELAXATION
102
What role does acetylcholine play in blood vessels?
Acetylcholine UPREGULATES eNOS
| This leads to steady vasodilation
103
Give an example of a nitric oxide donor.
SNP - sodium nitroprusside
104
Describe how arachidonic acid is produced.
Phospholipid ---------------> Arachidonic Acid
| Enzyme: Phospholipase A2
105
Describe how prostaglandins are produced from arachidonic acid.
Arachidonic acid -------------> Prostaglandin H2
Enzyme: COX1 + COX2
Prostaglandin H2 can then be converted to:
o Thromboxane (by Thromboxane Synthase)
o Prostacyclin (by Prostacyclin Synthase)
106
Describe how leukotrienes are produced from arachidonic acid.
Lipoxygenase enzymes convert arachidonic acid to: LTA4, LTB4, LTC4 and LTD4
107
What are the leukotrienes that are produced by the lipoxygenase enzymes and what effect does LTD4 have?
LTA4, LTB4, LTC4 and LTD4
| LTD4 causes BRONCHOCONSTRICTION
108
What therapy blocks the action of LTD4?
Montelukast Therapy
109
What enzyme produces arachidonic acid from DAG?
DAG lipase
110
Describe the mechanism of action of prostacyclin.
Prostacyclin binds to a receptor on smooth muscle cells and activates ADENYLATE CYCLASE ---> increase in cAMP ---> activate PKA ---> relaxation
111
Where is thromboxane produced?
Endothelial Cells
| Platelets
112
What are the two types of receptor for thromboxane and where are they found?
```
Alpha = Platelets
Beta = Smooth Muscle Cell
```
113
Describe the mechanism of action of thromboxane on vascular smooth muscle cells.
Thromboxane binds to Beta receptor on smooth muscle cell and activates PLC
PIP2 ---> IP3 + DAG
Increase in Ca2+
VASONCONSTRICTION
114
What effect does endothelin-1 have on endothelial cells?
Endothelin-1 can bind to beta receptors on endothelial cells and cause ACTIVATION OF eNOS (leading to VASODILATION)
115
What effect does endothelin-1 have on smooth muscle cells?
CONSTRICTION
116
What two types of receptors does endothelin-1 have?
Alpha and Beta receptors
117
What is the mechanism of action of endothelin-1 on vascular smooth muscle cells?
Alpha and Beta receptors on smooth muscle are linked to PLC.
| Endothelin-1 can bind to either and the result is CONTRACTION
118
Describe the production of angiotensin II.
Renin is released by juxtaglomerular cells
Renin converts angiotensinogen (produced by the liver) to angiotensin I
Angiotensin I is converted to Angiotensin II by ACE (mostly found in the lung endothelium)
119
What effects do angiotensin II have?
```
Increase Vascular Resistance:
o Vasoconstriction
o Increase sympathetic activity
Increase Water Retention:
o Increase sodium reabsorption
o Increase vasopressin secretion
o Increase aldosterone production
```
120
What other action does ACE have other than converting angiotensin I to angiotensin II?
It breaks down bradykinin
121
What is the mechanism of action of bradykinin on endothelial cells and what effect does it have?
Bradykinin binds to its receptor on endothelial cells.
PLC: PIP2 ----> IP3 + DAG
Results in UPREGULATIONG OF eNOS -----> increase in NO -----> VASODILATION
122
How do we go about increasing the diameter of blood vessels?
Increase NO by:
o Stimulate the production of NO
o Give an NO donor (e.g. SNP)
123
Describe the mechanism of action of viagra.
NO works by activating guanylyl cyclase, which then converts GTP ---> cGMP
The increase in cGMP causes relaxation (vasodilation)
cGMP is eventually broken down by PHOSPHODIESTERASE to GMP
Viagra is a PHOSPHODIESTERASE INHIBITOR
124
How does aspirin affect the synthesis of prostaglandins?
Aspirin causes irreversible inhibition of COX enzyme
| This reduces the conversion of arachidonic acid to prostaglandin H2 and hence decreases production of prostaglandins.
125
What is the effect of low dose aspirin on prostacyclin and thromboxane production?
Maintains high prostacyclin production while decreasing thromboxane production
126
Why does low dose aspirin have this effect?
Thromboxane is mainly produced by platelets, which have NO NUCLEUS
So the platelets can't produce more COX. Aspirin irreversibly binds to the COX in the platelets and the platelets can't make more COX to compensate.
Endothelial cells can make more COX so their prostacyclin levels remains high.
127
What is the problem with designing calcium channel blockers and what is the solution?
A calcium channel blocker needs to be designed such that it doesn't interfere with the calcium channels in the heart.
Solution: the affinity of the calcium blocker to the channel is dependent on MEMBRANE POTENTIAL
Smooth muscle cells have a MORE POSITIVE membrane potential than cardiomyocytes
128
Where the baroreceptors located?
Carotid sinus + aortic arch
129
What happens if there is an increase in baroreceptor firing?
This decrease the discharge of the sympathetic nervous system leading to a decrease in blood pressure and heart rate.
130
What neurotransmitter do all parasympathetic neurones release?
Acetylcholine
131
What is the most common neurotransmitter released at the effector end of a sympathetic neurone and what are some exceptions?
Noradrenaline
Exceptions: the adrenal medulla acts as a specialised post-ganglionic neurone as the chromaffin cells produce mainly adrenaline (80%) and noradrenaline. Sympathetic neurons to sweat glands release acetylcholine.
132
What are the two catecholamines?
Noradrenaline
| Adrenaline
133
Describe the two methods of uptake of catecholamines from the synaptic cleft and state the two enzymes involved in their breakdown.
They are either taken up into the presynaptic neuron that released them or into extraneuronal tissue.
Enzymes = Monoamine Oxidase (MAO) and Catechol-O Methyltransferase (COMT)
134
How are the adrenorecepors divided?
Alpha - excitatory on smooth muscle cells
| Beta - relaxant on smooth muscle cells + stimulatory on heart
135
Where are beta 1 receptors located?
Heart Muscle
| GI tract
136
Where are beta 2 receptors located?
Bronchi
Vasculature
Uterine Smooth Muscle
137
Where are alpha 1 receptors located and what is their main function?
Post-synaptic membrane - they mediate VASOCONSTRICTION
138
Where are alpha 2 receptors located and what is their function?
They are located on the presynaptic membrane and are involved in negative feedback.
Some are post-synaptic on smooth muscle cells and cause VASOCONSTRICTION (like alpha 1 cells)
139
Describe the structure of the adrenoreceptors.
Alpha 1 = Gq protein linked (PLC)
| Alpha 2 + Beta 1 + Beta 2 = Adenylate Cyclase (G alpha)
140
How do the effects of cAMP on smooth muscle, platelets and cardiomyocytes vary?
Increasing cAMP is:
o INHIBITORY = smooth muscle + platelets
o STIMULATORY = cardiomyocytes (unique)
141
Which adrenoreceptors do noradrenaline and adrenaline act on?
```
Noradrenaline = a1 + a2 + b1
Adrenaline = ALL the adrenoreceptors
```
142
State two synthetic compounds that can act on the adrenoreceptors and which adrenoreceptors do they act on?
```
Isoprenaline = b1 + b2 (pure beta agonist)
Phenylephrine = a1
```
143
What is the effect of a) noradrenaline, b) adrenaline and c) isoprenaline on systolic BP, diastolic BP, mean BP and heart rate?
```
Noradrenaline = increase, increase, increase, decrease
Adrenaline = increase, decrease, increase, increase
Isoprenaline = increase, decrease, same, increase
```
144
What three elements regulate renin release?
Amount of sodium reaching the macula densa cells
Blood pressure in the pre-glomerular vessels
Sympathetic activity can increase renin release
145
Describe ways in which the renin-angiotensin system can be inhibited.
ACE inhibitors - prevent conversion of angiotensin I to angiotensin II
Angiotensin II type I receptors (AT1) antagonists - prevent angiotensin II from exerting its effects
146
What type of receptor is an Angiotensin II Type 1 (AT1) receptor?
G protein coupled receptors (Gi and Gq)
147
What is the rapid pressor response of angiotensin II?
Direct vasoconstriction
Enhanced action of peripheral noradrenaline
Increased sympathetic discharge
Release of catecholamines from adrenal medulla
148
What is the slow pressor response of angiotensin II?
Happens over weeks or months
Increased sodium reabsorption
Increased release of aldosterone
Altered renal haemodynamics - renal vasoconstriction + enhanced noradrenaline effects in the kidney
149
Describe the effects of angiotensin II on the heart.
Increased preload and afterload
| Increased vascular wall tension
150
Why don't ACE inhibitors completely wipe out angiotensin II production?
There is another pathway that converts angiotensin I in to angiotensin II.
This reaction is carried out by CHYMASES
151
What is another effect of ACE inhibitors other than reducing angiotensin II?
Reduce the breakdown of bradykinin
152
What effect do angiotensin II type 1 receptor antagonists have?
Selectively blocks the effects of angiotensin II
| It has NO effects on the bradykinin system because ACE is working perfectly fine
153
What is the effect of aldosterone?
Increase Na+ reabsorption
| Increase K+ and H+ secretion
154
What are two main stimuli for aldosterone release?
Angiotensin II
| Increased Potassium
155
What are some harmful effects of aldosterone release?
```
Hypertension -------> Heart Failure
Primary Hyperaldosteronism (associated with benign tumours of the adrenal cortex) = HYPERTENSION + no oedema
Secondary Hyperaldosteronism (excessive response of the body in heart failure and liver failure) = Low/Normal blood pressure + SEVERE OEDEMA
```
156
What is a potent stimulus for the sympatho-adrenal and renin-angiotensin systems?
FLUID LOSS (e.g. severe haemorrhage)
157
What heart rate is considered bradycardia and tachycardia?
```
Bradycardia = < 60 bpm
Tachycardia = > 100 bpm
```
158
What is the difference between segments and intervals?
Segments are isoelectric regions between two waveforms.
| Interval is the time between the start of one wave and the start of the next.
159
What is the sweep speed of ECG?
25 mm/s
160
How wide is a small square and a large square and what time interval does that represent?
Small Square = 0.04 s (1 mm)
| Large Square = 0.2 s (5 mm)
161
What's the duration and amplitude of a normal P wave?
```
Duration = < 0.11 s
Amplitude = < 2.5 mm
```
162
What is the duration of a normal PR interval?
0.12 - 0.2 s
163
What is the duration and amplitude of a normal QRS complex?
```
Duration = < 0.12 s
Amplitude = < 25 mm
```
164
What is the normal range for the cardiac axis?
-30 to + 90
165
What is the duration and amplitude of a normal Q wave?
```
Duration = < 0.04 s
Amplitude = < 25% of the total QRS complex
```
166
What is the duration of a normal QT interval?
0.38-0.42 s
167
What does a QRS complex with a large amplitude indicate?
Ventricular Hypertrophy
168
What are the ECG features of sinus tachycardia?
Normal waveforms
Abnormally fast resting heart rate
Atrial and Ventricular Rate = 200 bpm
169
What are the ECG features of atrial fibrillation? Include atrial rate and ventricular rate in your answer.
ABSENT P WAVES (may get an oscillating baseline)
Irregular ventricular rhythm (duration between QRS varies)
Could be high or normal ventricular rate
QRS complexes are normal
Atrial Rate = 350-600 bpm
Ventricular rate = 100-180 bpm
170
What are the ECG features of atrial flutter?
SAW-TOOTHED BASE LINE
No isoelectric line - shows constant atrial activity
Regular ventricular rhythm - one in every few atrial depolarisations will get conducted down to the ventricles
QRS normal + regular ventricular rhythm
Atrial Rate = 250-350 bpm
Ventricular Rate = 150 bpm (with 2:1)
4:1 is also common
171
How is atrial fibrillation different to atrial flutter?
Atrial flutter has a regular ventricular rhythm
172
What is atrioventricular nodal reentrant tachycardia?
When a local circuit is created within the AV node
173
What is atrioventricular reentrant tachycardia?
Local circuit is within the atria and the ventricles
174
What are the ECG features of AVNRT and AVRT?
Lots of QRS complexes
No clear P wave
QRS complexes are RAPID and IRREGULAR
You get simultaneous depolarisation of the atria and ventricles so you get instantaneous P wave and QRS complexes
175
What happens in AVNRT?
Depolarisation is rotating within the AV node
| Then it re-enters and causes simultaneous atrial and ventricular contraction
176
What is preexcitation syndrome and what is a defining feature of the ECG?
Defining Feature = DELTA WAVES
Some people are born with a congenital connection between the atria and the ventricles called an ACCESSORY PATHWAY
This allows early depolarisation of the ventricles leading to slurring of the QRS complexes
This gives an abnormally short PR interval
177
State a cause of preexcitation syndrome.
Wolff-Parkinson-White Syndrome
178
What is the treatment to remove the accessory pathway?
Radio frequency ablation
179
What are the three types of atrioventricular nodal block and how do they vary?
```
1st degree = prolonged PR interval
2nd degree (Mobitz type 1 and type 2) = some conduction gets there but it's slow
3rd degree = complete heart block
```
180
What is an ECG feature of grade 1 AVN block?
Prolonged PR interval
181
What is the difference between Mobitz type 1 and Mobitz type 2 atrioventricular nodal block?
2nd degree block = some of the beats from the atria do NOT reach the ventricles
Mobitz type I = gradual prolongation of the PR interval culminating in a dropped beat
Mobitz type II = fixed PR interval and then a dropped beat (you do NOT see gradually prolonging of the PR interval)
182
What is the ECG feature of 3rd degree atrioventricular nodal block?
There is NO conduction from atria to ventricles
ECG shows COMPLETE DISSOCIATION between QRS complexes and P waves
Ventricles fire on their own as a protective mechanism
183
What is the main ECG feature of bundle branch blocks?
QRS complex WIDENS
| It takes longer to depolarise the ventricles
184
How do you distinguish between RBBB and LBBB on an ECG?
WilliaM MarroW
RBBB = V1 + V2 = rabbit ears
LBBB = V1 + V2 = deep S waves
185
What are the ECG features of ventricular tachyarrhythmia?
Rapid, regular, broad QRS complex pattern
186
What are the ECG features of ventricular fibrillation?
Broad QRS complexes that are VOID OF ANY PATTERN
187
What divisions of blood vessels has the largest cross-sectional area?
Capillaries
188
How does the amount of blood stored in the veins change during exercise?
Exercise causes VENOCONSTRICTION leading to a decrease in the amount of stored blood, so there is more venous return.
189
State the equation relating blood flow, pressure difference and resistance.
Blood Flow = pressure difference/resistance
190
Where does the biggest drop in blood pressure take place?
In the arterioles
191
What three variables determine resistance to blood flow?
Fluid viscosity
Vessel radius
Length of tube
192
Describe how blood normally flows in vessels.
Normal blood flow is laminar - blood flows fastest in the middle and slowest around the outside.
193
What is shear rate?
The velocity gradient at any time
194
What is shear stress?
Velocity gradient x viscosity
195
What are the effects of a) high, and b) low shear stress?
High = promotes endothelial survival
| Low (turbulent) = promotes endothelial proliferation, which affects vasoconstriction, platelet aggregation, coagulation
196
What are the equations for pulse pressure and mean arterial blood pressure?
Pulse Pressure = SBP - DBP
| Mean Arterial Blood Pressure = DBP + 1/3 PP
197
How do aortic and ventricular pressure differ and what is the reason for this difference?
Once the aortic valves close, ventricular pressure falls but aortic pressure only falls slowly during diastole because the elasticity of the aorta buffers the pressure.
198
What is the name given to the dampening effect of the aorta?
Windkessel Effect
199
What are the consequences of a decrease in arterial compliance?
Pulse pressure will increase
200
State the Law of Laplace.
When the pressure within a vessel is kept constant, tension is directly proportional to the radius.
T = PR
201
What does circumferential stress equal?
Circumferential stress = tension/wall thickness
| Circumferential stress = PR/h
202
What is compliance?
Change in volume of the vessel per unit change in pressure.
203
Describe how aneurysms are linked to the Law of Laplace.
The vessel radius increases meaning that greater wall tension is needed to withstand the internal pressure. If the structure of the wall is damaged and it can't have the required tension, then the vessel will continue to dilate.
204
How do the compliance of arteries and veins differ?
Veins are a lot more compliant
205
What is the difference between the blood pressure in the ankle compared to the hand?
Blood pressure in the ankle is much greater than in the hand
206
Why don't we faint every time we stand up due to blood pooling in our leg veins?
Standing causes activation of the sympathetic nervous system, which stiffens and constricts the veins resulting in greater venous return to the heart.
Constricted arteries means there is an increase in TPR to maintain blood pressure.
There is also a slight increase in heart rate and force of contraction.
207
What are the two pumps that facilitate the movement of venous blood back to the heart?
Skeletal muscle pump
| Respiratory pump
208
What neurotransmitter do all parasympathetic neurones release?
Acetylcholine
209
What neurotransmitters could sympathetic neurones release?
Noradrenaline, adrenaline or acetylcholine
210
What are the three ways of regulating blood flow?
Local controls (autoregulation), circulating hormones, autonomic nervous system
211
Describe the two theories of the local mechanisms of controlling blood flow.
Myogenic Theory - the vascular smooth muscle responds to stretch and constricts to maintain the blood flow
Metabolic Theory - if there is reduced flow, metabolites build up in the blood and signal to the smooth muscle to dilate. When the vessel dilates, the metabolites are washed away and the stimulus is removed.
212
State two molecules produced in the endothelium that cause vasodilation.
Nitric Oxide and Prostacyclin
213
State two molecules produced in the endothelium that cause vasoconstriction.
Thromboxane A2 and Endothelin-1
214
State five hormones that regulate blood flow.
```
Atrial Natriuretic Peptide
Kinins (e.g. bradykinin)
Vasopressin
Angiotensin II
Noradrenaline
```
215
What effects does the sympathetic nervous system have on the cardiovascular system?
Increased sympathetic activity increases heart rate, increases force of contraction and decreases the vessel radius (increases resistance)
216
What effect does the parasympathetic nervous system have on the cardiovascular system?
It decreases heart rate
| Causes vasoconstriction of the coronary arteries
217
The distribution of sympathetic nerve fibres is not even. Where do you find more sympathetic nerve fibres?
There are more sympathetic nerve fibres in the spleen, gut, kidneys and skin because there is more potential to divert blood away from these organs without causing damage. There are fewer sympathetic fibres in the skeletal muscle and brain.
218
What adrenoreceptors could circulating adrenaline bind to?
Beta-2 and alpha-1 (at high concentrations)
| Binding to beta-2 has a vasodilator effect but then binding to alpha-1 has a vasoconstricting effect
219
Where is the vasomotor centre located?
VMC is located bilaterally in the reticular substance of the medulla
The lateral portions control heart rate and contractility
Medial portions transmit signals via the vagus nerve
220
What neurotransmitter is involved in controlling vessel radius?
Noradrenaline - from the sympathetic innervation
221
What are the three ways of controlling vessel radius?
Local responses
Circulating hormones
Sympathetic innervation
222
What are the three ways in which stroke volume can be increased?
Starling's Law (increased venous return to the heart)
Increased plasma adrenaline and noradrenaline
Increased sympathetic innervation
223
Describe the mechanism of action of noradrenaline on the heart.
Noradrenaline binds to the beta-1 adrenergic receptor, which causes activation of adenylate cyclase and the upregulation of cAMP leading to the activation of PKA. PKA phosphorylates, hence activates, the L-type calcium channel, sarcoendoplasmic reticulum calcium ATPase, sarcoplasmic reticulum calcium release channel
224
How do respiratory movements affect cardiac output?
Inspiring decreases the intrathoracic pressure meaning that the pressure on the blood vessels is decreased so the blood flows more easily into the heart and hence it increases the stretch on the heart (preload) so cardiac output increases (Starling's Law)
225
What nerves carry information from the two baroreceptors to the vasomotor centre?
Carotid Bodies - Glossopharyngeal nerves
| Aorta - Vagus nerve
226
What is the consequence of increased baroreceptor activity?
Parasympathetic activity mirrors baroreceptor activity. Increases baroreceptor activity leads to increased parasympathetic activity and decreased sympathetic activity. The increase in parasympathetic activity leads to a reduction in heart rate.
227
What are the effects of a decrease in sympathetic activity on the heart?
Decrease in sympathetic activity decreases heart rate and decreases force of contraction of the heart. This also increases the blood vessel radius and decreases resistance.
228
What is the point in the baroreceptor response?
To maintain blood pressure
229
Why is gravity a problem for the cardiovascular system?
Gravity pushes a column of blood down from the head to the toes causing distention in the veins lower down in the body and increasing the volume of blood in the venous reservoir.
230
Why is blood pressure measurement taken from the arm?
Because it is level with the heart. When standing up, the blood pressure will decrease above the heart and increase below the heart so at the level of the heart, gravity would cause less of a change in pressure.
231
How does standing up affect blood pressure and why?
The blood pressure increases below the heart and decreases above the heart because gravity pushes a column of blood down from the head to the toes.
232
How does the change in posture affect fluid movement?
As gravity pushes blood down the body, there is an increase in capillary hydrostatic pressure meaning that more fluid leaves the capillaries and enters the interstitial compartment. This means that there is reduction in effective circulating blood volume so there is decreased venous return to the heart.
233
Explain how standing up affect venous return to the heart?
Blood pools in the distensible veins and fluid leaves the circulatory system due to the increased hydrostatic pressure so there is a decrease in the venous return to the heart and hence less ventricular filling and less stretching of the muscle fibres (preload) so the force of contraction is decreased (Starling's Law).
234
What is haemorrhage?
Reduction in actual circulating blood volume.
235
What are the three main responses to haemorrhage?
Increased heart rate
Increased heart contractility
Organ specific vasoconstriction
236
What is the compensatory mechanism that takes place in the capillaries to preserve fluid volume?
Autotransfusion - more fluid is retained in the capillaries (because the hydrostatic pressure is decreased due to the decrease in fluid volume but the colloid osmotic pressure is the same) - this means that less fluid leaves the capillaries and more fluid is reabsorbed.
237
State three hormones that are important in the response to haemorrhage?
Angiotensin II
Vasopressin
Aldosterone
238
What is the action of angiotensin II?
Angiotensin II is a powerful vasoconstrictor - it will decrease the amount of blood flowing to the kidneys and hence it will decrease urine output
239
Where do aldosterone and vasopressin act?
Kidney Collecting Duct
240
What are the effects of aldosterone?
Aldosterone causes the loss of K+ into the urine and the retention of Na+ and water
241
What are the overall effects of these three hormones?
Reduced blood flow to the kidneys causing reduced urinary output
Increased fluid retention to preserve blood volume and pressure
242
What percentage fluid loss can these compensatory mechanisms cope with?
Around 30%
243
Describe a mechanism that causes local vasodilation.
Active Hyperemia - if there is a lot of metabolism going on in a tissue, it will use up a lot of oxygen and glucose. The uptake of oxygen and glucose is detected by the tissue and it causes an increase in vessel radius.
244
What are the two afferent inputs to the medullary cardiovascular centre?
Preprogrammed pattern - autonomic response in anticipation of exercise
Chemoreceptors in the muscle - detect a changing environment
245
How does exercise affect TPR? What is the overall change?
Exercise causes a lot of vasodilation (e.g. to the skeletal muscle and the skin (to radiate heat away)) but there is some organ-specific vasoconstriction (spleen, GI tract). The overall effect is a DECREASE in TPR.
246
How does exercise affect CO? What is the overall change?
Increased sympathetic activity increases heart rate and contractility and the muscle activity causes increased venous return to the heart and so increased preload. However, there is an increase in hydrostatic pressure so more fluid is lost to the interstitium and fluid is lost as sweat. Overall there is an INCREASE in CO.
247
State the equation relating TPR, BP and CO. What is the overall effect of exercise on blood pressure?
BP = CO x TPR
| The increase in cardiac output is GREATER than the decrease in TPR and so there is an INCREASE IN BLOOD PRESSURE
248
What is the threshold for hypertension?
140/90 mm Hg
249
How does blood pressure change with age?
Systolic increases fairly linearly
Diastolic plateaus and then decreases
The difference between systolic and diastolic increases
250
What is the difference between primary and secondary hypertension? Which one is more common?
Primary/Essential Hypertension - has no known cause (95% of all hypertension)
Secondary Hypertension - has an underlying cause
251
Give some examples of secondary hypertension.
Renal Artery Stenosis
Conn's Syndrome (inappropriate secretion of aldosterone)
Pheochromocytoma (tumour of the adrenal medulla causing increased production of catecholamines)
Oral Contraceptive Pill
Liddle's Syndrome
252
Give some lifestyle risk factors of hypertension.
Obesity, Smoking, Alcohol, Salt Intake
253
What part of the CO = MABP/TPR equation is most affected in hypertension?
There is an increase in TPR caused by decreased arterial compliance
Normal cardiac output
Normal blood volume
254
State three causes of an increase in TPR.
Active narrowing of arteries - vasoconstriction
Structural narrowing of arteries - due to remodelling
Loss of capillaries
255
What organ has a major influence on hypertension?
Kidneys - hypertension is strongly associated with impaired renal flow and blood flow
256
What is congestive heart failure?
The inability of the heart to adequately pump blood at normal filling pressures.
257
What can hypertension do to large arteries?
Arterial hypertrophy
Promote atherosclerosis
Aneurysms - thrombosis and haemorrhage
258
What does hypertension do to the microvasculature?
Hypertension causes a decrease in capillary density and a subsequent elevation of capillary blood pressure
259
What becomes present in the urine in hypertensive people?
The kidneys are a target for damage due to hypertension. It leads to renal dysfunction leading to the presence of albumin in the urine (microalbuminuria). The concentration of albumin in the urine is proportional to the systolic blood pressure.
260
What are the two main mechanisms involved in haemostasis?
Platelets and Clotting Cascade
261
What happens in primary and secondary haemostasis?
Primary - platelet activation and aggregation - formation of an unstable platelet plug
Secondary - stabilisation of the plug with fibrin
262
Define coagulation.
The process by which blood is converted from a liquid to a solid.
263
What cells secrete Von Willebrand Factor?
Endothelial cells and platelets
264
What is exposed when the endothelial layer is damaged?
Subendothelial layer - collagen
265
How can the subendothelial layer be recognised?
The Von Willebrand factors bind to the collagen and the GlpIb receptors on the VWF bind to platelets
GlpIa receptors on the platelets can bind directly to the collagen
266
When the platelets are activated what do they release?
ADP and prostaglandins
267
What receptors become available on the platelets to allow fibrinogen to bind?
GlpIIa and GlpIIIb
268
Describe the effect of thrombin on the formation of the primary platelet plug.
Thrombin stimulates the activation of platelets so that they aggregate.
269
Describe the changes in the morphology of the platelets that take place when they are activated.
The platelets become more spiculated and their membrane changes composition. Phospholipids that were on the inside of the membrane move to the outside, which is important because they bind to coagulation factors. The platelets express GlpIIa and GlpIIIb receptors that can bind to fibrinogen.
270
Where are clotting factors, fibrinolytic factors and inhibitors synthesised?
Mainly in the LIVER
Von Willebrand Factor is produced in high concentration by the endothelial cells
Factor V is produced by megakaryocytes
271
Which clotting factors are cofactors?
Factor 8 and Factor 5
272
Describe the extrinsic pathway.
The extrinsic pathway is activation of factor 10 to 10a by Tissue factor bound to Factor 7 and calcium. This is the normal physiological activation of the clotting cascade.
273
What are factor 1 and factor 2 more commonly called?
Factor 1 = Fibrinogen ---> Fibrin
| Factor 2 = Prothrombin ---> Thrombin
274
What protein breaks down fibrin clots and what is its precursor? How is it activated?
Plasmin - the precursor is plasminogen
Plasminogen is converted to plasmin by the action of Tissue Plasminogen Activator (tPA)
tPA doesn't usually come into contact with plasminogen but when a fibrin clot forms, it assembles tPA and plasminogen on its surface so they come into contact and plasminogen is converted to plasmin.
275
What products can be given in therapeutic thrombolysis of myocardial infarction?
tPA (tissue plasminogen activator) and bacterial activator streptokinase
276
What are the two main coagulation inhibitory mechanisms?
DIRECT inhibition - antithrombin
| INDIRECT inhibition - Protein C inhibition pathway
277
What factors are inhibited by antithrombin?
Factor 2a, 9a, 10a and 11a
| It is a broad scale clotting factor inhibitor
278
Describe the effect of heparin.
Heparin accelerates the action of antithrombin
279
What are factor 8 and factor 5 activated by?
Trace amounts of thrombin
280
Describe the protein C inhibitory pathway.
Thrombin, once produced is usually involved in clot formation, activating platelets and activating factor 8 and factor 5.
Thrombin can binds to thrombomodulin (a protein on the surface of the endothelium) which changes its specification.
It then activates Protein C and Protein S, which then inactivate Factor 8 and Factor 5. This is the second anticoagulant mechanism.
281
What are the consequences of Factor V Leiden?
Factor V Leiden is a common polymorphism in the population. Factor V Leiden can't be inactivated as well as wild type Factor V. If protein C can't inactivate the factor V leiden as well, there is increased risk of thrombosis.
282
State four failures of coagulation inhibitory mechanisms that cause increased risk of thrombosis.
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor V Leiden
283
What clinical feature is common to all bleeding disorders?
Easy bruising
284
What constitutes the unstable platelet plug?
Exposed collagen - von Willebrand factor - platelets
285
A disease of primary haemostasis could affect what components of the unstable platelet plug?
Vessel wall - ageing and steroids can damage the endothelium
Von Willebrand factor - vWF disease means that you have no vWF
Platelets - warfarin and other drugs affect platelets. Thrombocytopenia.
286
Describe the pattern of bleeding of a defect in primary haemostasis.
IMMEDIATE - prolonged nose bleeds, easy bruising, menorrhagia, prolonged gum bleeding
287
What is a characteristic clinical feature of thrombocytopenia?
Petechiae
288
What is the main role of secondary haemostasis?
To produce fibrin from fibrinogen and stabilise the platelet plug by forming an insoluble mesh around it.
289
Why is there a lag between the administration of a tissue factor trigger and the thrombin burst?
This is when cofactors and clotting factors are synthesised.
290
What happens in haemophilia?
Deficiency of factor 8 or factor 9. Massively slows down the production of thrombin and so there is no real thrombin burst. Not much fibrin mesh is formed and so the clot is not stabilised.
291
State some other causes of problems with secondary haemostasis.
Liver disease (failure to produce clotting factors), drugs, consumption of clotting factors
292
What is DIC?
Disseminated intravascular coagulation - widespread activation of the coagulation cascade
Leads to consumption of the clotting factors - that's why it's also called consumptive coagulopathy
293
What is haemophilia defined as?
Failure to generate fibrin to stabilise the platelet plug
294
Describe the pattern of bleeding of defects in secondary haemostasis.
DELAYED - people with defects in secondary haemostasis are generally fine with small cuts. They bleed deeper into joints and muscles. Do NOT tend to bleed excessively from small cuts (because the primary haemostasis is fine)
295
What is the clinical hallmark of haemophilia?
Haemarthrosis - bleeding into joints
296
State some defects of clot stability.
```
Excess fibrinolytic (tPA)
Deficient antifibrinolytic (antiplasmin)
```
297
What are the possible clinical consequences of thromboembolism?
Thrombophlebitic syndrome
| Pulmonary hypertension
298
How does risk of thrombosis change with age?
Increases
299
What are the three components of Virchow's triad?
Hypercoagulability
Vessel wall injury
Stasis
300
Why is pregnancy associated with an increase in the risk of thrombosis?
Pregnancy involved reduced mobility and reduced flow and a decrease in protein S meaning that blood becomes procoagulant.
301
What is the only circumstance in which thrombolytic therapy is given? Why is it not given more often?
STROKE
| Because giving thrombolytic therapy increases the risk of bleeding.
302
Define atherosclerosis.
Chronic inflammatory disease of the arteries
303
What are the three layers of blood vessel walls and what is contained in each layer?
Tunica intima - endothelial cells
Tunica media - smooth muscle cells
Tunica adventitia - vasa vasorum and nerves
304
What is the process by which endothelial cells know that they need to form a single layer?
Contact inhibition
305
State some roles of the endothelial cells.
Angiogenesis
Vascular tone and permeability
Thrombosis and haemostasis
306
Where does leukocyte recruitment normally take place? Why does this normal recruitment of leukocytes not cause atherosclerosis?
Post-capillary venules
Normally, the leukocytes will pass through the endothelium and digest the basement membrane and pass through to the tissues
307
How are the large vessels different to the post-capillary venules?
Beyond the endothelium there is a THICK layer which the leukocytes cannot get through so they get stuck in the sticky subendothelial space.
308
Briefly describe leukocyte recruitment.
Leukocytes have weak interactions via selectins. When the endothelium is activated, it will express chemokines that bind to receptors on the leukocytes and switches their integrins to the high affinity state and subsequent binding to its ligand on the endothelial cells. This allows leukocyte immobilisation on the endothelial surface and transmigration.
309
Describe the sequence of events starting from endothelial activation and ending with atherosclerosis.
Endothelial activation --> LDL infiltration --> oxidation of LDLs --> LDLs get stuck in the sticky subendothelial layer (consisting of collagen and proteoglycans) --> macrophages infiltrate --> macrophages phagocytose the LDLs and form foam cells --> foam cells accumulate and form fatty streaks
310
Where does atherosclerosis tend to occur?
Branching points of arteries
311
How does blood flow affect the endothelium?
Laminar flow gives a positive protective signal to the endothelium so the endothelium is in an anti-inflammatory and anti-thrombotic state (NO is produced). Promotes endothelial survival.
Turbulent flow switches the balance and makes the endothelium pro-thrombotic and pro-inflammatory. Promotes endothelial apoptosis.
312
What is angiogenesis?
The formation of new blood vessels by sprouting from pre-existing vessels.
313
What triggers angiogenesis?
Hypoxia
314
Why is angiogenesis, in the context of cardiovascular disease, related to the Janus paradox?
Angiogenesis is bad for atherosclerosis - angiogenesis is stimulated from the vasa vasorum which become fragile and allow more LDLs in
Angiogenesis is good for myocardial infarction - therapeutic angiogenesis could reoxygenate ischaemic tissue downstream of an occlusion
315
What is cell senescence?
Growth arrest that halts the proliferation of ageing and/or damaged cells
This is protective against cancer because it prevents damaged cells from proliferating
316
What is the problem with cell senescence?
Senescent cells can develop a pro-inflammatory phenotype
317
What molecule in red wine has anti-inflammatory properties?
Resveratrol
318
Describe the difference in the function of macrophages and smooth muscle cells in an atherosclerotic plaque.
Macrophages remove arterial tissue
| Smooth muscle cells deposit arterial tissue
319
Describe the effects of macrophages on smooth muscle cells.
Macrophages stimulate smooth muscle cell proliferation and makes the smooth muscle cells produce more collagen to strengthen the fibrous cap.
320
What are the two classes of macrophages and how are their roles different?
Resident - involved in maintaining homeostasis
| Inflammatory - kill microorganisms
321
What causes the oxidation of LDLs?
Free radicals
322
Describe what happens to LDLs after endothelial activation.
Endothelial activation increases the membrane permeability
LDLs enter and are oxidised by free radicals and become stuck in the subendothelial layer
OxLDLs are phagocytosed by macrophages to form foam cells
The foam cells accumulate and cause chronic inflammation
323
What is Familial Hyperlipidaemia? State two clinical features.
Massively elevated blood cholesterol level (20 mmol/L)
Autosomal recessive
Xanthoma (accumulations of foam cells in the skin)
Early atherosclerosis
324
What is the LDLR regulated by?
It is negatively regulated by intracellular cholesterol
325
What is the second LDL receptor?
Scavenger receptor - this is a pathogen receptor that accidentally binds to oxidised LDLs
326
What determines the function of the second LDL receptor?
The level of oxidised LDLs present
At relatively low levels of OxLDLs, the abnormal materials are taken up by macrophages and cleared safely by reverse cholesterol transport.
At high levels of OxLDLs, it triggers an inflammatory reaction
327
What eventually happens to the foam cells?
They eventually become full of fat and die by apoptosis releasing cytotoxic fat and contributing to the lipid necrotic core
328
What enzyme do macrophages have that affects oxygen?
NADPH Oxidase - reduces oxygen to make superoxide (O2-)
329
What does the superoxide end up producing?
Superoxide ends up producing hypochlorous acid (by the action of myeloperoxidase from hydrogen peroxide and chlorine)
330
What enzyme is involved in the production of HOCl and what other product can it produce?
Myeloperoxidase - also produces a more unstable form called peroxynitrite
331
What cytokines are released by macrophages?
IL-1 = upregulates VCAM-1 thus increasing leukocyte migration
332
What two growth factors are produced by macrophages and how do they affect smooth muscle cells?
Platelet derived growth factor (PDGF) = stimulates smooth muscle chemotaxis, survival and division
Transforming growth factor - beta = stimulates collagen synthesis
333
Describe how the normal function of a smooth muscle cell is different to the synthetic smooth muscle cell in atherosclerosis.
Normal - more contractile filaments and less collagen deposition
Synthetic - fewer contractile filaments and more collagen deposition
PDGF and TGF-beta can make the VSMC become the synthetic phenotype
334
What do the matrix metalloproteinases expressed by macrophages do?
They break down the collagen in the ECM and hence weakens the plaque
335
What are the characteristics of unstable plaques?
Thin fibrous cap
Reduced VSMC and collagen content
Infiltration of activated macrophages expressing MMPs
Large, soft, eccentric lipid-rich necrotic core
336
What is a master transcription factor involved in atherosclerosis and what does it stimulate?
Nuclear Factor Kappa B - stimulates matrix metalloproteinases and stimulates inducible nitric oxide synthase
