John Palmer’s Chest Pain

Starling’s Law

1. What variables can change cardiac output?1

2. What are after-load and preload?2

3. What is Starling’s Law?3

4. What is the main difference between cardiac muscle and skeletal muscle?4

5. Why is cardiac muscle more sensitive to stretch than skeletal muscle?5

6. Why is Starling’s Law important?6

7. Where would you calculate blood pressure in the lungs?7

8. What happens to stroke work and end diastolic pressure (i) In exercise (ii) in heart failure?8

9. Why is cardiac output low in a dilated heart?9

1 Filling pressure of right heart, function of the heart-lung unit (e.g. pulmonary edema?), Resistance to outflow from left ventricle, Influence of ANS on B1 receptors

2 After-load is the tension on the wall of the left ventricle during ejection. Preload is the resistance to outflow from the left ventricle, these are related to the volume of blood that goes into the ventricle during diastole.

3 The rule that energy released during contraction depends on the initial fibre length, so stretching the muscle and therefore increasing the sarcomere length (Z band to Z band) (e.g. by increasing venous influx) also increases force.

4 Cardiac muscle contains tropomyosin, which covers the myosin cross bridge binding sites until removed by Ca2+ and TnC to expose binding site. Cardiac muscle is made up of intercalated disks, doesnʼt tire like skeletal muscle and relies on Ca2+ in the cells to maintain a prolonged AP ʻplateauʼ which is not the case in skeletal muscle (which only depends on Na+ and K+ for action potentials).

5 As the muscle stretches, troponin C (part of the troponin complex present in cardiac muscle) becomes more sensitive to calcium.

6 Left and right sides need to be equal/balanced or fluid will be forced in or out of lungs. (Pulmonary Edema)

7 Pulmonary venous pressure is considered to be equal to lung pressure

8 In exercise = stroke work and EDP increase because the heart is distended, in heart failure both decrease because the heart is grossly distended and has gone beyond optimum stretch potential

9 Although more stretch equals more force this is only true to a point. In a grossly distended heart Laplaceʼs Law (pressure = 2x tension/radius), so a greater radius actually means less pressure.

10.What does an increase in blood volume do to CVP and CO?10

11.What effects does digoxin have on the heart and venous system?11

12.How do you work out CO from HR and SV?12

13.How do you work out SV from EDV and ESV?13

Initiation of the Heart Beat

1. What is the equilibrium potential for potassium?14

2. What are the approximate lengths (in milliseconds) for a nerve AP and a cardiac AP?15

3. What causes cardiac muscle to contract?16

4. ... and to relax?17

5. Which class of anti-arrhythmic drugs (i) block Ca2+ channels, (ii) block K+ channels (iii) block Na+ channels?18

6. Why is there a bigger spike in voltage in an action potential through the Purkinje fibres than in the ventricles?19

10 Both increased

11 Increases contractility and decreases CVP as more blood pumped into arteries.

12 Heart rate (bpm) x stroke volume

13 ESV minus EDV gives you the difference (i.e. the volume pumped out of the heart in one stroke/beat)

14 -90mv, K+ maintains the resting potential for cardiac muscle

15 Nerve (3ms), Cardiac (300ms)

16 Na+ channels open, influx of Na+, fast upstroke from -90mv, channels start to close when charge gets nearer to 0mv and when over 0mv, voltage gated L-type Ca2+ channels open which causes a large influx of Ca2+

17 Ca2+ gradually decays during ʻplateauʼ region of AP and when dips below 0mv then K+ channels open up, efflux of K+ speeds up repolarisation to -90mv (which is the equilibrium potential of K+)

18 Class IV block Ca2+ channels, Class III block K+ and class I block Na+

19 Purkinje fibres are specialised conduction vessels and have a greater surface area so can absorb Ca2+ more quickly.

7. How is conduction of a cardiac action potential slowed by the AV node?20

8. What is the Ca2+ threshold (i.e. voltage at which Ca2+ channels are opened) in the SAN?21

9. What do delayed rectifier K+ channels have to do with heart rate?22

10.Why is there little inherent decay of K+ in skeletal muscle, whereas there is in cardiac muscle?23

11.What do ‘If ’ channels do?24

12.How does parasympathetic stimulation slow the heart rate?25

13.How are cardiac muscle cells connected to ensure electrical transmission between them?26

14.What factors (outside the cell) might slow the rate of conduction of the wave of depolarisation?27

15.What is the speed of AP conduction in the atria, AVN and bundle of His?28

20 AV node cells do not contain fast upstroke Na+ channels so only depolarize when resting potential naturally decay is large enough to be picked up by the Ca2+ channels, upstroke is entirely driven by calcium and is therefore slower than in the rest of the heart.

21 -45mv (resting potential -90mv)

22 Delayed rectifier K+ channels in the SAN control the rate of decay of the cardiac action potential. The channels gradually decay, so K+ enters at a slower rate, meaning RMP can be maintained for a shorter period of time and HR increases.

23 The 1B (basal current, i.e. the current outside the cell) in skeletal muscle cells is much lower than in cardiac cells. This is the reason K+ equilibrium potential is reached in cardiac muscle but not skeletal muscle.

24 ʻIfʼ channels control how much Na+ enters the cell, and therefore how much K+ comes out (via basolateral Na+/K+ATPase), so blocking ʻIfʼ blocks decay of action potential because less K+ leaves cell. Sympathetic stimulation causes increased firing of action potentials by increasing activity of If channels, increasing rate of AP decay and so frequency of APs.

25 Blocking K+ channels in the SAN, causing hyperpolarisation and so takes longer for natural decay of AP and longer to repolarise.

26 Intercalated disks are connected by a desmosome, between these are gap junctions containing ʻconnexonsʼ which are channels that mediate electrical conduction between cells.

27 Capacitance level of membrane (ability to store charge), and resistance of gap junctions/connexons between cells.

28 Around 0.1m/s in atria, 0.05 in AVN and 4m/s in Bundle of His, mainly need to know that AVN is much slower.

16.What is the effect of Wolf Parkinson White?29

17.Why is noradrenaline described as a positive inotrope?30

18.What happens if you lose the SAN?31

19.Describe the mechanism of ‘calcium induced calcium release’32

20.What causes repolarisation?33

21.Which channel removes calcium from the cell between beats?34

22.What would happen to HR if you blocked Na+/K+ATPase (e.g. Digoxin)?35

23.What is the mechanism of B receptor agonists increasing cardiac contractility (e.g. isoprenaline, adrenaline)?36

24.What inhibits the mechanism in (23)?37

Electrocardiogram

1.Which lead is normally looked at to obtain a basic (4 lead) ECG?38

29 Extremely high heart rate because of accessory route of conduction (like an extra AVN)

30 It stimulates Ca2+ entry by acting on B1 receptors, causes increased level of cAMP which increases force of contraction.

31 The heart will continue to beat but the rate will be slower. Under normal circumstances the fastest transmission wins which is the SAN

32 Calcium released initially from T-tubule lumen activates calcium channels on the sarcoplasmic reticulum. These greatly increase Ca2+ further leading to rapid upstroke.

33 K+ efflux as well as SRCA (Sarcoplasmic Reticulum Calcium ATPase) removes Ca2+ from cytosol back into SR, this process is accelerated by noradrenaline (which also stimulates Ca2+ re-entry) because it increases the speed/frequency of APs and so increases the heart rate.

34 Na/Ca anti-port, 3Na+(in)/Ca2+(out)

35 Digoxin blocks Na+(out)/K+(in)ATPase in cardiac muscle, which has a knock-on effect on Na+(in)/Ca+(out) channels because the cell becomes saturated with Na+. Less Ca2+ leaves the cell meaning the AP is extended and the length of action potential (and so cardiac force) is increased.

36 Increase cyclic AMP which causes more Ca2+ to enter cell, increasing contractility. (cardiac glycosides such as Digoxin work in the same way).

37 Parasympathetic stimulation and release of acetylcholine (despite being the main neurotransmitter in the body and having an excitatory effect on striated muscle, acetylcholine has an inhibitory effect on the heart)

38 Lead II

2.What are the approximate lengths of P-R interval, QRS complex and Q-T interval?39

3.What do the P-R interval and QRS complex represent?40

4. What could a long QRS complex indicate?41

5. What does the ST/QT segment represent?42

6. Why does the ECG trace not remain peaked for the whole time the ventricles are contacted?43

7. What is the purpose of the right leg lead (4th lead) on a 3 lead ECG?44

8. Where are the 3 leads attached on the body on a 3 lead ECG(each lead is attached to 2 places on the body)?45

9. Why does the T wave (repolarisation) appear on the same side of the line as the QRS complex (depolarisation)?46

10.What could an inverted T wave indicate?47

11.What is a vector?48

12.What are the 3 types of leads on a 12 lead ECG and what are the main differences between these leads?49

39 P-R interval 120ms, QRS complex 80ms and Q-T interval 300ms

40 P-R is the delay in the AV node between atrial depolarisation and ventricular depolarisation, QRS complex is the time taken for the wave of depolarisation to activate all ventricular muscle.

41 Delays going from one bit of the ventricle to another (e.g. damage to ventricular muscle)

42 The space between ST and QT segments is approximately the plateau of the AP

43 An ECG trace only measures the difference in voltage between different parts of the heart, so it only produces a trace when there is a difference in voltage, during movement.

44 Earth wire - gets rid of electrical noise on the trace

45 Lead 1 = right arm and left arm, lead 2 = right arm and left leg, lead 3 = left arm and left leg

46 Endocardium (inside) has a longer action potential than the epicardium (outside), so whilst depolarisation goes from inside-out, repolarisation goes in the reverse direction outside-in.

47 current or recent ischemia

48 A line which has both amplitude and direction (like an ECG incorporates the height + the side of the flat line)

49 3 bipolar limb leads, 3 augmented unipolar limb leads, 6 horizontal unipolar limb leads. In bipolar leads both ends are sensing and in unipolar leads only one is sensing and one is an estimate (e.g. what voltage is likely to be midway between arm and leg).

13.What do AVR, AVL and AVF mean?50

14.Why would a septum which contracted after the ventricles be a problem?51

15.What is 1st degree heart block?52

16.What is 2nd degree heart block?53

17.What is 3rd degree heart block?54

18.What is left bundle branch block?55

19.What is ST elevation or depression and what does it indicate?56

20.What does a long QT interval tell you?57

21.What is hypertrophic cardiomyopathy?58

Haemopoesis and Types of RBC

1. What % of blood would you expect to be haemocrit?59

50 Augmented leads which look at different angles of the ʻtriangleʼ, (AVR - augmented right arm), (AVL - augmented left arm, AVF - augmented left leg (think ʻfootʼ))

51 Septum needs to contract first so blood can be pushed out effectively, septum contracting onto already contracted ventricles is a weaker force than ventricles.

52 Where conduction is very slow through the AV node. Shows as a wide P-R interval (distance between beats). Can be caused by drugs or excessive parasympathetic stimulation.

53 Where SAN is beating at normal rhythm but only around 1/2 or 1/3 beats getting through the AV node. You will see some additional P waves not conducting through into a QRS complex.

54 Where no signal is getting through the AV node at all. The AV node has been completely destroyed. The heart will still beat but beats will originate in the ventricles and work at a completely different rate than the atria (i.e. slower) so the P waves and the QRS complex will be out of sync.

55 Slow route to left ventricle so results in a long QRS. Often follows MI.

56 A competing current is present following recent MI or ischemia because conduction is malfunctioned but tissue is not dead yet.

57 QT interval represents the time the ventricle is contracted before repolarisation, a long QT means heart rate is slow. Can be a sign of long QT syndrome (a 1/500 congenital disorder).

58 An enlarged left ventricle, can be the cause of sudden death in otherwise healthy individuals.

59 45% in a male, 35% in a female (roughly)

2. What are granulocytes and agranulocytes and what proportion of white blood cells are they?60

3. Why are red blood cells shaped in a bi-concave disk?61

4. What is the lifespan of a red blood cell?62

5. How does a normoblast differ from a reticulocyte?63

6. What could cause a low platelet count and how would you visibly notice this?64

7. What colour would reticulocytes stain histologically?65

8. What are alpha granules and dense granules?66

9. What is the average platelet lifespan?67

10.What are megakaryocytes?68

11.What do the 3 different granules in neutrophils contain?69

12.What property do neutrophils have that allows them to survive in hypoxic or dead tissue?70

60 The two groups of white blood cell, agranulocytes have a non-lobed nucleus (includes neutrophils 40-70%, eosinophils (1-6%) basophils (less than 1%) and granulocytes have a lobed nucleus (includes lymphocytes 20-40% and monocytes 2-6%).

61 Allows them to have +20-30% surface area compared to a sphere of similar volume and to squeeze and deform through capillaries

62 Around 120 days, old ones removed by liver and spleen

63 Normoblast = last stage of development of a red blood cell, still has a few mitochondria and ribosomes which will be lost when the cell becomes a reticulocyte (mature red blood cell)

64 Low platelet count causes spontaneous bruising, could be a result of disturbed marrow function or chemotherapy having destroyed marrow and platelet production.

65 Cresyl blue and remaining RNA form blue precipitate

66 Both are granules found in platelets. Alpha contain various clotting factors including factor 4 and platelet derived growth factor whereas dense granules contain seratonin

67 8-10 days

68 Giant cells with large multi-lobed nuclei whose ER vesicles eject cytoplasm surrounded by membrane which become platelets

69 1 - acid hydrolases (for breakdown of decaying matter), myelopepsidase. 2 - inflammatory mediators which attract white cells, 3 - gelatinase (denatured collagen), helpful to break through basement membrane and putting in adhesion proteins into membrane allowing cells to bind (e.g. to vessel endothelium)

70 Have few mitochondria and most respiration is anaerobic

13.How do eosinophils attack larger cells?71

14.What causes degranulation in basophils?72

15.What are the main functions and properties of monocytes?73

16.What is the difference between B lymphocytes and T lymphocytes?74

17.Where does haemopoesis (blood formation) take place in the embryo at (i) 2.5 weeks, (ii) 5 weeks, (iii) 4 months +75

18.What do pluripotent stem cells (precursor cells) require to transform them into red blood cells?76

Haemeostasis1. What is primary haemostasis?77

2. What activates platelets by increasing their Ca2+ levels causing them to release cyclo-oxygenase?78

3. What does cyclo-oxygenase do after this?79

4. What is adhesion?80

71 Contain hydrolytic lysosomal enzymes such as peroxidase, which punch holes in larger cells and help break through the basal membrane and kill the cell.

72 Basophils and mast cells degranulate when the IgEs they are coated in couple with variable region on antibody complex

73 Monocytes are highly phagocytic and motile, have a very long lifespan, function is also antigen presentation and cytokine secretion.

74 B lymphocytes have a surface antibody receptor (for antigens) which cause expansion of the cell and secretion of more antibody. T lymphocytes are cell mediated (only work by directly touching other cells, CD4 express antigen and CD8 kill the complex formed).

75 2.5 weeks = ʻblood islandsʼ, 5 weeks-4months = liver, 4 months+ = bone marrow

76 IL3 and Stem cell factor

77 Where damage to the endothelium sets of a local mechanism causing

78 Von Willebrand factor (a.k.a. GP1b) released from damage to endothelium

79 Causes the release of thromboxane A (TXA2)

80 Where platelets have bound to each other or the endothelium on all 3 possible binding sites (Von Willebrand, GP1V and Integrin a2b1). This is the initial stage of blood clot formation

5. What does thromboxane A (TXA2) do?81

6. What is the effect of ADP released from dense granules on blood clotting?82

7. What is the name of the molecules which bridge the gap between platelets?83

8. What is aggregation?84

9. What substances inhibit platelet aggregation?85

10.After the platelets have been joined to the endothelium and to each other, what substance reinforces the clot structure?86

11.Which enzyme converts soluble fibrinogen into insoluble strands of fibrin?87

12.Which factor converts pro-thrombin to thrombin?88

13.What are the two main functions of thrombin?89

14.Where are the majority of tissue factors produced?90

15.Whereabouts in the cardiovascular system are tissue factor bearing cells (such as fibroblasts and monoblasts, which start clotting cascade) found?91

81 Release stimulated by cyclo-oxygenase. TXA2 causes release of dense granules from platelets which contain seratonin and more VWF, ADP and factor 5. TXA2 and seratonin are local vasoconstrictors which act to limit blood loss by constricting affected vessel.

82 ADP binds to P2Y12 receptors and activates GPIIb and GPIIIa receptors on platelet which bind to fibrinogen

83 Fibrinogen

84 The process of joining platelets together with fibrin to form an advanced blood clot

85 NO and prostacyclin (vasodilators) because they increase cAMP and cGMP inside the cell. Also tissue factor pathway inhibitor (TFPI) which binds F10 inhibiting F10-F7 complex

86 Fibrin (derived from fibrinogen)

87 Thrombin

88 Factor VII activates Factor X which combines with Factor V to produce prothrombinase, an enzyme which converts prothrombin (precursor) into thrombin (enzyme)

89 1/ convert fibrinogen into fibrin, 2/ to form additional cross bridges between platelets in clot to make it hard and insoluble

90 In the liver

91 Behind the endothelium, so when the endothelium becomes damaged these cells are exposed to platelets in the blood and the clotting process begins

16.What does tenase do?92

17.What causes the retraction of the clot?93

18.What is activated by heparans on endothelial cells, and the drug heparin, to inactivate factors 9-12?94

19.Under normal circumstances (i.e. when there is no damage to the endothelium), what is activated to inhibit factors 5 and 8 and prevent the clotting process?95

20.And in the case of haemostasis, what stops this from happening?96

21.How does aspirin act to inhibit the clotting process?97

22.How does heparin act to inhibit the clotting process?98

23.Why is fondaparinux used as an alternative to heparin?99

24.How does warfarin act to inhibit the clotting process?100

25.What are the 3 parts of Virchow’s triad of causes of clotting?101

26.What is the visible difference between an arterial thrombus and a venous thrombus?102

92 Activates factor 10, tenase is activated by combination of factors 8 and 9

93 When Fibrin polymerises into long threads which are cross linked by F13. The clot becomes hardened and insoluble

94 Antithrombin

95 Active Protein C in complex with Protein S, activated by thrombomodulin, prevents the conversion of fibrinogen into fibrin

96 Protein C via plasminogen activator inhibitor

97 Aspirin irreversibly inhibits cyclo-oxygenase (which if not inhibited causes the release of ADH, TXA2 and Seratonin from dense granules)

98 Heparin activates antithrombin which inhibits factors 9-12

99 Because it is a synthetic polysaccharide as opposed to heparin which is animal-derived and has more negative side effects in terms of immune reactions.

100 inhibits vitamin K reductase which is required for factors to dock with phospholipids on the cell surface. Takes longer to have an effect than other anticoagulants. Requires regular checking because doses vary hugely for different people.

101 Endothelial vascular damage (to arteries), low blood flow or stasis in veins and hyper-coagulability

102 Arterial = characterised by lots of platelets so appears white, veins have a higher coagulability because of slower flow which means the clot captures more red blood cells and appears red. Arterial clots are associated with atherosclerosis whilst venous ones from immobility e.g. DVT on a plane

27.How would a white clot be treated?103

28.Give 5 examples of clotting diseases?104

Microcirculation and Capillary Dynamics

1. Which areas of the cardiovascular system count as microcirculation?105

2. What are the functions of lymphatic capillaries?106

3. What are the 3 types of capillary?107

4. What are the routes in and out of the continuous capillaries?108

5. What is the glycocalyx?109

6. How is the blood brain barrier different from other capillaries?110

7. How many litres of fluid are pumped through the capillaries per day, and how much moves across membranes in both directions?111

103 With quick action anticoagulants e.g. aspirin, clopidogrel or by an angioplasty procedure (PCI/stent)

104 Haemophilia A or B, Vitamin K deficiency (uses clotting factors to synthesise vitamin K), Antiphospholipid syndrome, Von Willebrand Disease (deficiency of VWF), Factor V Leiden (mutant factor 5 cannot be inactivated by APC so results in hyper-coagulability)

105 Terminal arterioles (which act as ʻsphinctersʼ when they constrict to reduce flow to adjacent capillaries), Capillaries and Venules (not arteries or arterioles)

106 absorb fluid and protein and return these to the blood via the thoracic duct, take up foreign micro-organisms from the blood and transport these to the lymph nodes where they can be killed

107 Continuous (main type, present in most tissues and has a monolayer of endothelium, tight junctions and is the least permeable), Fenestrated (has slightly porous endothelium so is more permeable, found in glomerular filter), Sinusoid (the most permeable because it has big gaps in the endothelium, found in liver because it allows large molecules to diffuse in and out)

108 Tight junctions for moderate sized molecules and diffusion of small molecules and transport in vesicles for anything large like proteins. 90% of water travels through tight junctions and 10% through ʻwater channelsʼ in the bilayer. Gasses are liphophobic and can therefore dissolve in lipid which can easily diffuse membrane, small solutes are liphphobic and must travel through the tight junctions (since the cell wall is a lipid bilayer).

109 A layer that coats the whole lumenal (inside) side of the capillary endothelium. It is a negatively charged gel which acts as a molecular filter for the capillary epithelium

110 The blood brain barrier prevents the diffusion of most hydrophilic solutes (e.g. proteins). Some key substances (salt, glucose, amino acids) have to go through specific transport proteins. So the composition of the CSF is tightly regulated.

111 4000L pumped per day but 80,000L travels across the membrane in both directions, the net loss is only 8L/day which is mostly returned to the blood through the lymph. If these pressures are imbalanced, edema of the tissues will result.

8. What is the approximate pressure gradient out at the arterial end of a capillary, and in at the venous end?112

9. What is the main gradient driving water into the capillaries?113

10.What is Starling’s equation?114

11.What is the reflection coefficient of a substance?115

12.Why does net movement of fluid differ for different areas of the body?116

13.What might make fluid movement out of the capillary (filtration) lower than normal for a given area?117

14.Which vein does lymph ultimately drain into?118

15.What drives lymph flow?119

16.What could cause edema to develop?120

17.What is Kwashiakoor?121

18.What is Elephantiasis?122

112 Arterial 40mmHg, venous -15mmHg

113 Capillaries tend to contain more protein than tissues around them so draw water in with osmotic gradient. Proteins with a high reflection coefficient (e.g. blood protein albumin) tend to exert a higher osmotic pressure

114 Illustrates the role of hydrostatic and oncotic pressures on movement of a fluid across a capillary membrane. It is ʻMovement of fluid proportional to (capillary pressure - interstitial pressure) - refraction coefficient (capillary oncotic pressure - interstitial oncotic pressure)ʼ.

115 A measure of the oncotic pressure exerted by a unit of a particular solute

116 Varies for differing pressures according to gravity (e.g. higher pressure in legs/feet therefore more likely to see edema in legs), also type of capillaries (e.g. fenestrated capillaries in glomerulus, net movement out)

117 If arteriole leading to capillary was constricted (e.g. afferent arteriole), osmotic gradient of interstitial fluid surrounding capillary, control of permeability by glycocalyx

118 Lymph flows to thoracic duct and then into subclavian vein

119 Fluid forced into lymph and moved along by muscle contraction, valves prevent backflow

120 Blocked lymph nodes due to inflammation, decrease in oncotic pressure of blood, increase in capillary hydrostatic pressure gradient, hypervolemia.

121 Edema development because of protein malnutrition therefore decreased oncotic gradient in blood and loss of fluid from the blood. Presents as bloating and edema particularly in abdomen.

122 Where a worm gets into the lymph and blocks lymph vessels causing gross swelling as lymphatics unable to remove fluid. The same effect may also happen if areas of lymph are surgically removed.

Infarction and Embolism

1. Why are most infarcts arterial rather than venous?123

2. What is the difference between a ‘white infarct’ and a ‘red infarct’?124

3. Where are white infarcts most likely to occur?125

4. What is a transmural infarct?126

5. Name the 3 main coronary arteries?127

6. What is a sub-endocardial infarct?128

7. What is the most obvious histological change in necrotic tissue?129

8. What ECG changes would you typically see following an MI: (i) 1-8 hours post MI, (ii) 8hours-2days post, (iii) more than 2 days post?130

9. What enzymes might you notice in raised levels in the plasma following MI?131

10.What are the two main agents (drugs) associated with thrombolysis?132

11.What is the difference between a thrombus and an embolism?133

123 Because there is usually only one artery supplying a given area of tissue whereas veins more frequently anastemose.

124 White infarct from arterial occlusion and show up white because of lack of blood cells in region. Red infarct is the opposite (e.g. pulmonary infarct) where blood has become trapped in necrotic tissue and not been able to leave (e.g. venous infarct).

125 In solid tissues e.g. heart, spleen, liver which are supplied by a single artery prone to blockage

126 Distribution of infarct over close to 100% of whole area supplied by blocked artery (not 100% because gas exchange may occur by diffusion at peripheries).

127 Left anterior descending, left circumflex, right coronary

128 Where only the inner 1/3 or 1/2 of ventricular wall is ischemic following infarct.

129 Cells lose their nucleus

130 1-8 hours, ST segment elevation, 8h-2days Q wave increased, over 2 days T wave inversion. May notice other arrhythmias for 1-2 days post caused by re-entry in dead heart tissue.

131 Cardiac troponins, creatinine kinase

132 Streptokinase and Tissue Plasminogen Factor (TPA)

133 Thrombus has not moved, embolism has moved (embolus, e.g. clotting in legs and goes to lungs or brain)

12.What is commonly responsible for development of thromboembolism in an atherosclerosed artery?134

13.What is hyperkinesis?135

14.How would you identify a fat embolism histologically?136

15.Which are the two leg veins most likely to produce a DVT resulting in fatal pulmonary embolism?137

16.What class of drugs would you use to treat ‘white’ thrombi and what for ‘red’ thrombi?138

Pharmacology: Angina

1. What is angina and why does it occur?139

2. What is the difference between unstable angina and vasospastic angina?140

3. What are the main physiological targets of treatment for angina?141

4. What kind of drugs might be given to induce these effects in answer to (3) and what are their effects?142

134 Rupture of atherosclerotic plaque, release of TXA2, fibrinogen, 5 hydroxytriptamine, platelet activating factor, adenosine diphosphate which promote platelet aggregation

135 When contractility in the remaining myocardium increases following infarction

136 Use Oil Red O to make the fat more visible

137 Iliac and femoral veins

138 White are platelet rich and are treated with antiplatelet drugs (e.g. Aspirin, Clopidogrel) and red, RBC rich thrombi are treated with anticoagulants (e.g. Heparin, or Warfarin (for long term)).

139 Pain coming from the heart via nerves in the chest, arm or elsewhere. Occurs when the O2 demand of the heart is above supply.

140 Unstable angina is due to non-occlusive thrombus i.e. doesnʼt block artery fully whereas vasospastic angina is the spasm of coronary artery which has probably got atherosclerosis leading to poor perfusion

141 1/ Decreasing the oxygen need of the heart (decreasing cardiac work), 2/ Dilation of the coronary arteries, 3/Decreasing heart rate

142 B-blockers such as propanolol (non-selective) or atenolol (B1 selective) will decrease heart rate and contractility, GTN spray (Glyceryl trinitrate) which relaxes smooth muscle cells and produces nitric oxide in presence of ALDH-2, Ivabradine which inhibits ʻIfʼ (which determines pacemaker potential in the SAN) so decreases heart rate

5. What is the mechanism of nitric oxide in causing vasodilation?143

6. What are the possible negative effects of GTN?144

7. What defines a drug as having 1st pass metabolism?145

8. How long does GTN spray take to produce an effect and how long does this last?146

9. If you wanted to give nitrates over a longer period than GTN spray what might you use?147

10.What are reactive oxygen species and what do they do?148

11.How do Ca2+ channel blockers help protect against heart damage?149

12.Name 2 Ca2+ channel blockers150

13.What is a dangerous side effect associated with using Ca2+ channel blockers?151

14.What effect would a K+ channel agonist have on cardiac action potentials?152

143 Normally calcium/calmodulin stimulates release of nitric oxide synthase which catalyses the production of nitric oxide from L-arginine and NADPH, nitric oxide then stimulates conversion of GMP to cGMP in the presence of guanate cyclase. Increased cGMP decreases the Ca2+ level and decreases SM contraction. (In the case of GTN treatment, the GTN is metabolised by ALDH-2 to release NO)

144 headache, red face (dilation), fainting (also from dilation and decreased CO)

145 It cannot be given orally because it is totally metabolised by the liver and so to have an effect is usually taken sublingually (under tongue) so absorbed into bloodstream, or by spray so absorbed in lungs.

146 1-2 mins for effect, lasts 30 mins

147 GTN patch or isorbide di-nitrate, although the risk is that if administered over an extended period that that the body develops tolerance to GTN

148 ROS are given off during oxidative stress (e.g. after UV exposure or MI), they cause generalized cell damage and inhibit ALDH-2 so GTN cannot produce NO as effectively if given after an MI.

149 Ca2+ channel blockers decrease the height of the action potential and so the force of contraction in cardiac muscle, they also reduce the contraction of SM in veins and arteries (so decrease TPR) and therefore the O2 demand of the heart.

150 Verapamil or diltiazem

151 Reflex tachycardia (fast heart rate) induced by the relaxation of the heart

152 K+ controls the resting potential of the AP, blocking it would lengthen the action potential by hyperpolarising the cell but in doing so would decrease the heart rate, reducing cardiac work overall.

15.What would you use to treat vasospastic angina and why would you not use atenolol?153

16.What is the mechanism of statins given to reduce LDL cholesterol?154

17.What negative side effects may be associated with statins?155

Pharmacology: Anti-Thrombosis Drugs and MI

1. What are the main causes of thrombus?156

2. What is the main type of drug used to treat venous thrombi?157

3. What anti-thrombolytic treatment would be used for rapid effect?158

4. What is the main dangerous side effect of all anticoagulants such as heparin, warfarin and clopidogrel?159

5. By what mechanism does warfarin inhibit blood clotting?160

6. What is fondaparineux?161

7. What are hirudin and bivalirudin?162

153 Atenolol works on B1 receptors which affect HR and contractility, they have no vascular effect. You would use vasodilators such as Ca2+ channel blockers or GTN

154 Block liver synthesis of LDL cholesterol by inhibiting hydroxymethyl glutaryl CoA reductase (HMG-CoA). Liver also takes up more LDL cholesterol from plasma so the level in blood plasma drops.

155 Muscle breakdown and liver damage

156 Atherosclerosis or lack of movement leading to slow blood flow, injury to vessel wall or hyper-coagulability of blood (drug, congenital)

157 Anticoagulants which cause antithrombin and active clotting factors IIa, IXa and IIIa to form aggregate complexes which are inactive.

158 Heparin given as IV bolus (as not absorbed orally), acts within a few minutes inhibiting numerous clotting factors. Disadvantage is unpredictable dose-response.

159 Hemorrhage. This is why all warfarin patients have to regularly attend INR clinics.

160 It blocks the regeneration of Vitamin K (NADH--> NAD+). Less vitamin K is produced which is normally used in carboxylation of factors II, VII, IX and X so that they can bind calcium and produce a blood clot. If vitamin K is absent, these factors are still produced by they are unable to bind calcium.

161 A low molecular weight heparin which acts by inhibiting factor Xa, increasing the effect of antithrombin. Given IV but more predictable than heparin so preferred.

162 Direct thrombin inhibitors, similar to substances found in vampire bats

8. What is the mechanism of aspirin?163

9. What is the mechanism of PY12 inhibitors?164

10.What is the mechanism of GpIIb/IIIa receptor inhibitors?165

11.What are fibrinolytic/thrombolytic drugs and how do they work?166

12.What might an elevated ST segment on an ECG indicate?167

13.Within what length of time would you need to implant a PCI/stent in a patient’s coronary artery if there was a blockage that had lead to MI?168

Pharmacology: Arrhythmias

1. What are the main causes of atrial fibrillation?169

2. What are the ranges for bradycardia (low heart rate) and tachycardia (high)170

3. What is the difference between a supra-ventricular (SVT) and a ventricular arrhythmia (VT)?171

4. Give 2 examples of SVT and VT and how they might be identified on an ECG?172

5. What is a latent or ectopic pacemaker?173

163 Aspirin irreversibly inhibits cyclo-oxygenase so blocks synthesis of TXA2 and PGI2

164 Block ADP binding to platelet receptors, so stop activation of platelets by ADP released from dense granules

165 Platelets are activated by do not adhere to each other and the endothelium as well.

166 Break down fibrin so break up the actual clot itself. Work by promoting the formation of plasmin which degrades fibrin clots.

167 ST segment is between depolarisation and repolarisation so length of AP, can indicate myocardial ischaemia as heart is having to work harder (longer contraction).

168 1-6 hours for best results, survival rate decreases rapidly after 1 hour.

169 Atrial dilatation, heart failure, hypertension, overactive thyroid

170 Low = below 60bpm, High = above 100 bpm

171 Supraventricular = origin in or above AV node. Ventricular = origin in ventricle, purkinje fibres or bundle of His.

172 SVT = Atrial flutter (P waves and QRS dissociated), Atrial Fibrillation - irregular beat and no P.waves, VT = Ventricular Tachycardia (no organised electrical activity), Ventricular fibrilation = (wide and abnormal QRS, 100-200 bpm)

173 When an area of the heart other than the SAN starts producing a beat, i.e. has the fastest action potential and sets the heart rate.

6. What produces an ectopic beat?174

7. What is triggered automaticity?175

8. What is re-entry and where is it likely to occur?176

9. What is Wolff Parkinson White syndrome?177

10.What are the 4 classes of anti-arrhythmic drugs?178

11.What are the mechanisms by which adenosine and digoxin take effect on the heart?179

12.How do Na+ channel blockers such as the local anesthetic lidnocane reduce the heart rate?180

13.What causes the tendency of some parts of the heart to become pacemakers in the case of ischaemia?181

14.What is a radiofrequency ablation?182

Physiopathology of Heart Failure

174 Where localised low plasma K+ causes decreased diastolic potential (does not effectively repolarise), so the threshold potential for Ca2+ channels is reached sooner and causes production of ectopic beat. Often triggered by ischaemia.

175 Excessive increases in Ca2+, often drug induced, trigger premature APs

176 Where an impulse becomes ʻtrappedʼ in a loop around one region of the heart. Stimulates the tissue adjacent to it causing it to beat prematurely. Often occurs in damaged tissue around the edge of an infarct.

177 The presence of an additional pathway other than the AVN known as the Bundle of Kent which allows APs from the atria to the ventricles, causes a competing potential and arrhythmia. It is detected in the presence of a pre-excitation delta wave and can speed up the heart rate.

178 Class 1 = Na+ channel blockers (lidnocane), Class 2 = B receptor blockers (propanolol), Class 3 = AP Prolonging drugs (amiodarone), Class 4 = Ca2+ channel (verapamil)

179 Both slow AVN conduction whilst digoxin increases vagal activity so slows AV node conduction. They can also be used to block the isthmus (extra-channel) in re-entry.

180 Blocking the Na+ channel means conduction can only operate on Ca2+ so it raises the threshold for AP firing.

181 Ischaemia causes increased noradrenaline release which increases Ca2+ in cardiac cells, the heart has more of a tendency to depolarise under these conditions and one part may end up depolarising faster than the SAN. Noradrenaline and catecholamine also speeds up AVN conduction.

182 Medical procedure where re-entrant tissue pathway is destroyed to limit

1. What is the definition of heart failure?183

2. What is decompensation?184

3. Define ‘after-load’ and ‘preload’?185

4. What does angiotensin do to the preload?186

5. What is often the cause of right heart failure?187

6. What does an S3 S4 gallop indicate?188

7. What is ‘pitting’?189

8. What is ascites?190

9. Explain the difference between hypertrophy and hyperplasia?191

10.Why would the right ventricle take on a larger volume for a given EDP than the left ventricle at the same EDP?192

11.Why might a distended right heart not indicate right heart failure?193

183 Inability to provide adequate cardiac output to support the needs of the tissues

184 When eventually, in spite or because of compensatory mechanisms, heart failure is such that CO and BP begin to fall. Little things like stress or flu can set this off.

185 Afterload = tension developed in left ventricular wall during systole, Preload = the initial stretching of the left ventricle prior to contraction (i.e. sarcomere length prior to contraction), reflects filling volume.

186 Increases load on the heart by vasoconstriction, and increases blood volume so increases preload

187 Can occur in chronic pulmonary conditions where the right heart is having to work harder to pump blood to the lungs, right heart ultimately fails due to pressure overload. OR in congestive heart failure the right heart is having to work harder to support a failing left heart.

188 S3 is the blood rushing into the ventricles from the atria, S4 is caused by the atria forcefully contracting to fill an abnormally stiff hypertrophic ventricle. S3-S4 gallop indicates a high filling pressure.

189 Severe edema where pressing into the skin creates a ʻpitʼ like pressing into wet sand

190 edema in the peritoneal area, looks like a bloated belly

191 Hypertrophy is the increase in the size of cells to make the heart dilated/distended. You only have a certain number of cardiac cells and cannot create more of them. Hyperplasia is an increase in the number of cells of an organ.

192 Because the right heart has a thinner wall

193 Could have been distended compensating for a failing left heart without failing itself

12.What are typical hydrostatic pressures for the pulmonary vein and pulmonary artery?194

13.What causes muscle weakness and generalized weakness in heart failure?195

14.Why do mechanisms for increasing cardiac output during exercise not function properly in a failing heart?196

15.How would increased muscle mass (cardiac hypertrophy) appear on an ECG?197

16.What is the difference between a dilated heart and cardiac hypertrophy?198

Treatment of Heart Failure1. What are the possible adverse effects of using ACE 1 inhibitors?199

2. Why would you use Angiotensin II receptor blockers instead of Angiotensin I receptor blockers?200

3. What positive effect might using diuretics have on the respiratory system?201

4. What are the negative side effects on cardiac function can be caused by thiazide and loop diuretics?202

5. What could you do to reduce this effect?203

194 Vein 10mmHg, Artery 20mmHg

195 Not enough blood perfusing tissues because of failing heart but also because the compensatory mechanisms making up for failing heart constrict the arteries to skeletal muscle in an attempt to divert blood flow to the heart.

196 Because the heart is already compensating in this way, it is working at maximum output or even decompensating. It also becomes less sensitive to noradrenaline.

197 Rightward shift of cardiac index

198 In both cases the heart will appear ʻbiggerʼ but in hypertrophy this is because the cells are bigger and there is more muscle mass, in a dilated heart the wall has been stretched so much that it is actually thinner.

199 Hypotension, Renal Impairment (because angiotensin normally controls differential constriction of the afferent and efferent arterials – if this is taken away GFR can rise or fall to damaging levels), Hyperkalemia (because you’re not excreting enough K+)

200 Normally Bradykinin is broken down by ACE, ACE is active during the step between Ang 1 and Ang 2 so it is less active when Angiotensin 1 blockers are used. Angiotensin 2 blockers have no effect on bradykinin levels.

201 Increase exercise capability by reducing dyspnoea (breathlessness/pulmonary edema)

202 Excessive K+ loss leading to slower repolarisation and resulting arrhythmias

203 Give a K+ sparing diuretic in addition, spironolactone (aldosterone antagonist) or K+ supplements

6. What are the negative side effects of spironolactone?204

7. What is ivabradine?205

8. What are the main positive effects of B-blockers?206

9. What kind of drugs reduce afterload?207

10.What are cardiac glycosides and what is their mechanism?208

11.Why do cardiac glycosides not prolong survival in heart failure (apart from causing arrhythmias?209

12.Why might cardiac glycosides cause arrhythmias?210

13.How do B1 agonists work?211

14.What diagnosis would you make of an ejection fraction of (i) less than 45% (ii) more than 50% (iii) less than 40%212

15.How do PDE inhibitors work?213

Atherosclerosis

1. Name the 4 basic structural layers of a muscular artery?214

204 Gynecomastia, hyperkalaemia (because aldosterone normally causes K+ secretion) and renal dysfunction

205 An inhibitor of ‘If’ so slows heart rate and stabilises heart, reducing the chance of arrythmias

206 Negative inotropes which reduce cardiac remodelling and rennin release, decrease symptoms of heart failure

207 Vasorelaxants such as hydralazine and isosorbide dinitrate

208 Increase contractility by inhibiting K+(in)/Na+(out) pumps in cardiac muscle cells. More Na+ in cell reduces Ca2+ loss because it slows down the Na+(in)/Ca2+(out) pumps.

209 It is a positive inotrope so makes the heart work harder making symptoms worse. They are used to treat atrial fibrillation because they reduce AVN conduction.

210 Because they increase the excitability of the tissue and may lead to a delayed after polarisation

211 Opposite of beta blockers, they act like noradrenaline and stimulate release of adenylate cyclase which stimulates cAMP release which increases force and heart rate

212 Less than 45= moderate systolic dysfunction, greater than 50=diastolic dysfunction, less than 40 = severe systolic dyfunction

213 PDE III mediates the conversion of cAMP into 5-AMP (inactive form) so means cAMP retains its active form for longer

214 Endothelium, tunica intima, tunica media, tunica adventitia

2. Which parts of the artery structure does atherosclerosis affect?215

3. What is Monchebergʼs Medial Sclerosis?216

4. Describe the stages of formation of a fatty atheromatous plaque (not embolism)217

5. What are vasa vasora?218

6. What is intermittent claudication?219

7. What is the most common location for aneurysm?220

215 Intima and internal elastic lamina

216 Calcification of muscular arteries

217 Lipid crosses endothelium in high levels from blood, phagocytosed by macrophages (monocytes), high level of lipid present in macrophages in the intima, smooth muscle cells migrate from media to intima, these are modified under these condition so that they are also able to phagocytose lipid and start producing lipid rich collagen, collagen plaques then appear white, fatty plaque obscures media (SM) and therefore artery weaker, less able to constrict but gets blocked by lipid. May lead to aneurysm (abnormal dilatation and bursting) or embolism (clot).

218 Vessels which supply the adventitia and outer 1/3 of media (literally = ʻvessels of vesselsʼ)

219 Pain in calf muscles when walking, leg arteries narrowed by atherosclerosis and lactic acid builds up.

220 Abdominal aorta