Cardiovascular System Flashcards
1
Q
What is haemopoiesis?
A
Formation of the blood cells
2
Q
What is the lifespan of a red blood cell?
A
120 days
3
Q
What is the lifespan of a platelet?
A
7-10 days
4
Q
Where do the precursors of mature blood cells derive from?
A
Bone marrow.
In utero; yolk sac, liver and spleen, bone marrow
Children - all bones
Adults - axial skeleton
5
Q
Haemopoietic stem cells
A
They are pluripotent, so they replicate and differentiate into red cells, white cells, platelets and marrow stroma.
6
Q
Control of haemopoiesis
A
Replication and differentiation is stimulated by hormonal growth factors.
For red blood cells, the hormone is erythropoietin (EPO) which is used for renal failure therapy. White blood cells the hormone is Granulocyte-macrophage colony-stimulating factor (GM-CSF) used in chemotherapy. For platelets its thrombopoietin (TPO) drives production of platelets used in people who have low platelet count.
7
Q
Histological features of red blood cells (erythrocytes)
A
Simple anucleate cells with no mitochondria
Biconcave
7.5micrometer diameter
Contain haemoglobin glycolysis enzymes
8
Q
Haemoglobin
A
Carries oxygen from the lungs to the tissue. 4 globin chains each with its own haem group (O2 carrier)
Tetrametric protein with 2 alpha and 2 beta chains.
Allows O2 to reversibly combine with Fe2+ ions in an aqueous environment.
9
Q
Method of looking at haemoglobin: High performance liquid chromatography (HPLC)
A
Separates haemoglobin on basis of electrical charge
10
Q
Method of looking at looking at haemoglobin: Electrophoresis
A
Separates haemoglobin on basis of electrical charge
Acid and alkaline conditions
11
Q
Abnormalities of haemoglobin
A
Sickle cell disease (heterozygous dominant)
Lack of the gene for alpha/beta thalaessemia - beta is more common since this is the chain that changes from the baby form of Hb.
12
Q
What is the name for the condition where there is a deficiency of Hb?
A
Anaemia
13
Q
For men and women respectively, what are low levels of Hb? Why do women have lower levels of haemoglobin?
A
Men - <130g/L
Women - <110g/L
Women have lower levels due to menstrual bleeding
14
Q
What is acute blood loss?
A
Blood loss results in loss of red blood cells and plasma.
Initially the haemoglobin levels will be unchanged.
15
Q
Whart is a result of production failure of RBC?
A
Hypoplastic anaemia (not enough) Dyshaemopoeitic anaemia (ineffective production)
16
Q
Why could there be increased removal of RBC?
A
Blood loss or haemolytic loss (breakdown of RBC). This can be due to intrinsic (within RBC) abnormalities or extrinsic (outside RBC) abnormalities.
17
Q
Aplastic anaemia
A
Can be inherited or acquired for reasons such as idiopathic, chemical/drug, viral, radiation.
18
Q
Dyshaemopoietic anaemia
A
Multiple mechanisms e.g. anaemia of chronic disease
Defective haemoglobin synthesis.
Defective DNA synthesis.
19
Q
Haemolytic anaemia can be due to 2 reasons
A
Intrinsic RBC abnormalities
Extrinsic abnormalities
20
Q
Haemolytic anaemia + intrinsic RBC abnormalities
A
It can be acquired such as with PNH (haemolysis - breaking apart of RBCs) or it can be for hereditary reasons such as membrane disorders, enzyme disorders, and haemoglobin disorders.
21
Q
Haemolytic anaemia + extrinsic RBC abnormalities
A
Antibody mediated (AIHA) Mechanical trauma (DIC) Infections (Malaria) Chemicals (lead poisioning) Sequestration (hypersplenism)
22
Q
Iron deficency anaemia
A
This is the most common cause of anaemia caused by chronic bleeding in the gastrointestinal tract, poor diet, malabsorption, hook worm.
There is a reduction in mean amount of Hb in cell and cell volume.
23
Q
Types of white blood cell
A
Neutrophils Monocytes Lymphocytes Basophils Eosinophils
All cells except lymphocytes are termed phagocytes.
24
Q
What is the most abundant WBC?
A
Neutrophils
25
What do neutrophils do?
They phagocytose bacteria and foreign material by releasing chemotaxins and cytokines important in the inflammatory response.
26
What is the inflammatory response?
Increased temperature
Increased blood flow
Local pain
27
What happens when there is a decreased number of neutrophils?
Recurrent bacterial infections
28
Monocytes
Macrophages which also phagocytose bacteria+foreign material. The majority transit through the blood to the tissues. They are dendritic cells which present antigens to the immune system.
29
How do neutrophils and monocytes differ?
Monocytes are present in tissues.
30
What do basophils become?
Basophils migrate to tissues becoming mast cells.
31
What are mast cells?
Mast cells are filled with histamine containing granules and express surface IgE. They have an important role in the immune and allergic response.
32
Eoisinophils
Rare
| Special role in protection against parasites.
33
Where do B-lymphocytes mature?
Bone marrow of the rib
34
What percentage of lymphocytes in the blood do B-lymphocytes make up?
20%
35
Role of B-lymphocytea
Generate antibodies when stimulated by foreign antigens in the humoral immunity response.
36
Where do T-lymphocytes matures?
Thymus
37
What percentage of lymphocytes in the blood do T-lymphocytes make up?
80%
38
B-lymph have ??? receptors
| T lymph have ??? receptors
B - IgE
| T - TCR
39
Two types of T-lymph.?
Cytotoxic T-cells which target infected cells for death (cell mediated immunity).
T-helper cells stimulate the immune response of B-lymphocytes.
40
How does blood inside the vessels remain fluid?
Endothelial cells, anticoagulant pathway and fibrinolytic pathway actively keep it fluid. Platelets and proteins of the coagulation cascade circulate in an inactive state.
41
What is thrombosis?
When blood clots inside the vessel instead of outside the vessel as it should.
42
What do platelets contain?
Electron dense granules containing calcium, ADP/ATP and serotonin.
Alpha granules containing platelet derived growth factor (PDGF), fibrinogen, heparin antagonist (PF4) and VWF (von Willebrand Factor).
43
Platelets + primary haemostasis.
Platelets circulate in an inactive state. When there is damage to the blood vessel, they adhere to collagen via glycoprotein Ia on sub-endothelium.
Glycoprotein Ib and Glycoprotein IIIa bind von Willebrand Factor. Binding causes platelets to change shape and activate become elongated. Tethering of platelets causes them to activate further receptors on their surface which enables further crosslinking
44
Platelets + primary haemostasis.
Platelets circulate in an inactive state. When there is damage to the blood vessel, they adhere to collagen via glycoprotein Ia on sub-endothelium.
Glycoprotein Ib and Glycoprotein IIIa bind von Willebrand Factor. Binding causes platelets to change shape and activate become elongated. Tethering of platelets causes them to activate further receptors on their surface which enables further crosslinking with VWF and fibrinogen.
Activation releases contents and results in intracellular signalling causing platelets to release their stored granular contents. Aggregate to form a platelet thrombus (haemostatic plug). Lack of function leads to bleeding. Change in number leads to bleeding/thrombosis.
45
Platelet bleeding disorders: Bernard-Soulier syndrome
| Cause and impacts?
Deficiency of GPIb receptor
| Affects platelet adhesion
46
Platelet bleeding disorders: Glanzmann's thrombasthenia
| Cause and impacts?
Defect of GPIIb/IIIa receptor
| Affects platelet cross-linking and aggregation.
47
Platelet bleeding disorders: Hemansky-Pudlak
| Cause and impacts?
Defect in dense storage granules
| Affects Platelet activation and aggregation
48
When is there a reduction in platelet number?
Thrombocytopenia
Increased bleeding
Spontaneous bleeding
49
When is there a increase in platelet number
Thrombocytosis
Arterial thrombosis
Venous thrombosis
50
Plasma
Clear, straw coloured liquid left after cellular component of blood is removed. It is 90% water but also has salts, glucose and proteins.
51
Proteins in plasma
Albumin
Carrier proteins
Coagulation proteins
Immunoglobulins
52
Where is albumin produced?
The liver
53
What is the function of albumin?
To determine oncotic pressure of the blood and keep intravascular fluid in that space and keep the pressure within vessel.
54
What can a lack of albumin lead to?
Oedema
| seen in liver disease; nephrotic syndrome
55
What produces immunoglobulins?
B-lymphocytes
56
What are immunoglobulins?
Antibodies
57
Different classes of immunoglobulins?
```
IgG
IgA
IgM
IgE
IgD
```
58
What is the Coagulation Cascade?
Series of enzymes that circulate in an inactive state. They are sequentially activated in a 'cascade sequence' and convert soluble fibrinogen into insoluble fibrin polymer. This generates a stable clot.
59
What does inhibition of fibrin production lead to?
Bleeding
60
A sign of failure of coagulation proteins
Bleeding
61
A sign of overactive coagulation proteins
Thrombosis
62
What drugs affect platelet function? When are they used?
Aspirin
Clopidogrel
Used following a heart attack to reduce risk of further clots
63
Hemophilia A symptom
severe bleeding into muscles and joins
64
Why does Hemophilia A take place?
Deficiency of factor VIII, a blood clotting protein
65
How is Hemophilia A treated?
Recombinant factor VIII
66
Hemophilia A + genetics
X-linked condition
| Alternate generations
67
Hemophilia B
Severe bleeding into muscles and joints
68
Why does Haemophilia B take place?
Deficiency of factor IX
69
How is Hemophilia B treated?
Recombinant factor IX
70
Von Willebrand Disease
Usually mild bleeding disorder which is often unrecognised due to a deficiency in VWF
71
Affect of aspirin and clopidogrel on bleeding?
Affect platelet function by reducing it
72
Affect of chemotherapy on bleeding?
Reduces platelet numbers
73
Which drugs affect coagulation cascade?
Heparin - a natural anti-coagulant produced by basophils and mast cells which inhibits platelet function while inactivating various coaguation factors such as factor IX
Warfarin
oral anticoagulants
74
Affect of steroids on bleeding?
Steroids affect tissues making them weaker causing bruising and bleeding
75
Liver disease + Blood
Coagulation factors such as factor VIII and factor IX are synthesised in the liver so LD is often associated with bruising and bleeding and prolonged prothrombin time.
May also result in low platelets.
76
Vitamin K + blood
Necessary for functional activity of coagulation factors II, VII, IX and X. Warfarin interferes with the vitamin K activation pathway.
Manifests as prolonged prothrombin
77
Disseminated intravascular coagulation
Breakdown of haemostatic balance.
Simultaneous bleeding and microvascular thrombosis which is life threatening.
Can cause sepsis
78
Transfusion reactions
If the patient is transfused with red blood cells that have antigens on their cell surface which the patient lacks on their own RBCs, the new RBCs are seen as foreign and they are haemolysed.
79
Blood group A alleles and plasma antibodies
AA or AO
| Anti-B antibodies
80
Blood group B alleles and plasma antibodies
BB or BO
| Anti-A antibodies
81
Blood group AB alleles and plasma antibodies
AB
| No antibodies
82
Blood group O alleles and plasma antibodies
OO
| Anti-A and Anti-B antibodies
83
Other blood group
Rhesus system (Rh)
84
5 most important antigens in the Rhesus system
D C c E e
85
Which is the most clinically significant antigen in the Rhesus system?
D
Responsible for the most clinical issues associated with the system
Can either be present Rh D+ or absent Rh D-
86
Anti-D and pregnancy
If women who are Rh D antingen negative (dd) have a baby inside which has Dd genotype, and D-antigen negative mother is exposed to D antigen from baby's red blood cells, immunoglobins called IgG anti-D produced by the mother. As a result, baby causes transfusion reaction against mum. The IgG Anti-D can cross placenta and haemolyse the baby's red cells.
87
What are packed red cells?
Packed = plasma depleted
88
When are platelets administered medically?
On oncology wards to patients who have bone marrow failure.
89
What is HAS?
Human albumin solution
Physiological plasma expender
Used to increased oncotic pressure (liver disease, nephrotic syndrome) keeping fluid within vessels.
Can reduce oedema.
90
What is gastrulation?
Mass movement and invagination of the blastula to form 3 layers:
1. ectoderm
2. mesoderm
3. endoderm
91
What does the ectoderm eventually become?
Outside skin
Nervous system
Neural crest (which contributes to cardiac outflow and coronary arteries)
92
What does the mesoderm eventually become?
All types of muscle
Most systems
Kidneys
Blood
93
What does endoderm eventually become?
```
Gastrointestinal tract (including liver and pancreas, but not smooth muscle)
Endocrine organs
```
94
What does FHF stand for? What will it eventually become?
First heart field (future left ventricle)
The FHF generates a scaffold which is added by the second heart field and cardiac neural crest.
95
What does SHF stand for? What will it eventually become?
Second heart field (future outflow tract, future right ventricle, future atria)
96
During which days does the primitive heart tube form?
18-22
97
Why does the primitive heart tube begin to form?
Diffusion alone is no longer capable of sustaining the embryo
98
Where do progenitor heart cells originate from?
The epiblast
99
What happens on day 16?
Progenitor heart cells migrate through steak to the splanchic layer of lateral plate mesodemr. Cells specialise from lateral to medial to become different parts of the heart.
100
Where does the secondary heart field reside?
Splanchic mesoderm ventral to the pharynx. Cells extend laterally to form the left and right outflow.
101
What happens when the primary heart field cells are established?
They are induced by the pharyngeal endoderm to form cardiac myoblasts ad blood islands that develop into blood cells and vessels via vasculogenesis.
102
What happens from the blood islands
Blood islands unite into a horse-shoe endothelia lined tube surrounded by myoblasts. This is called the CARDIOGENIC region. The intraembryolic cavity (primitive body) surrounding it develops into the PERICARDIAL CAVITY.
The bilateral and parallel blood islands develop to form dorsal aorta (pair of longitudinal vessels).
103
What happens as the embryo folds head to toe and laterally (coupled with the rapid growth of the brain)
The heart and pericardial cavity move first to the cervical region and then to the thorax.
104
What happens to the developing heart tube after this
| poles
The developing heart tube receives venous drainage as its caudal pole and begins to pump blood out of the first aortic arch into the dorsal aorta at its cranial pole. It bulges more into the pericardial cavity.
105
What happens on day 22?
The heart begins to beat
106
What happens on day 23?
Heart tube lengthenes and begins to bend
107
As looping of the heart tube begins, what begins to appear?
Primordial structures.
The atrial portion (paired suture outside the pericardial cavity) forms a common atrium and is incorporated into the pericardial cavity.
The atriventricular junction remains narrow and forms the atrioventricular canal which connects the common atrium and the early ventricle.
108
What does the 'bulbis cordis' develop into?
The trabeculated part of the right ventricle.
109
What does the conus cordis (the mid-portion of the bulbus cordis) develop into?
The outflow tracts of the ventricles
110
Before cardiac separation, what is there?
one common atrium and one common ventricle
111
Process of cardiac separation
The cardiac septum forms and the septum primum extends from the endocardial cushions into the atria from the atrioventricular canal. The ostium primum (the opening between the septum and endocardial cushions) closes as the endocardial cushions extend whilst perforations appear in the upper end of the septum primum forming the ostium secondum, eventually being closed by overlap by the septum secondum. Septum secondum extends to form the superior atrial wall, where the foramen ovale is found. At birth, as the lungs become functional the left atrial pressure exceeds that of the right forcing the septum primum against the septum secondum. This forms the fossa ovalis.
112
Which two kinds of arteries are there?
Elastic and Muscular
113
Function of elastic arteries
Increase efficiency
114
Function of muscular arteries
Control distribution
115
What are the arterioles?
Terminal branches of the arteries
116
Examples of elastic arteries
```
Aorta
Brachiocephalic
Carotids
Subclavian
Pulmonary
```
117
What regulates blood flow in capillaries?
Precapillary sphincters
118
3 types of capillaries
Continuous
Fenestrated
Discontinuous
119
What drives embryonic vessel development
Angiogenic growth factors: (vascular endothelial growth factor, angiopoetin 1+2) which induce growth
Repulsive signals (plexin, semaphorin signalling, ephrin interactions) which prevent growth
Active signals - VEGF
120
How do you determine if a vessel is an artery or a vein? (receptor)
Ephrin-B2 receptor is only present on ARTERIES.
| Ephrin-B4 receptor is only present on VEINS.
121
What do the first and second 'aortic arches' become?
They become minor head vessels.
The first aortic arch becomes a small part of maxillary.
The second aortic arch becomes artery to ear
122
What do the third aortic arches become?
Become common carotid arteries and proximal internal carotid arteries.
Distal internal carotids come from extension of dorsal aortae.
123
What happens to the right dorsal aorta and right 4th aortic arch?
The right dorsal aorta loosens connection with midline aorta and the 6th aortic arch, remaining connected to the right fourth arch. It acquires branch of 7th cervical intersegmental artery, which grows into the right upper limb. The right subclavian artery is diverted from the right fourth arch, right dorsal aorta and right 7th intersegmental artery.
124
Left dorsal aorta and Left 4th aortic arch
The left dorsal aorta continues into trunk as the descending aorta.
The left 7th cervical intersegmental artery grows into the left subclavian artery. The left subclavian artery is diverted from the left fourth arch, left dorsal aorta and left 7th intersegmental artery.
125
6th aortic arch
Right 6th arch may form part of the pulmonary trunk
| Left arch forms ductus arteriosus - communication between pulmonary artery and the aorta.
126
Platelets and disease
```
Thrombosis
Myocardial infarction
Ischaemic Stroke
Critical leg ischaemia
Sudden death
```
127
What is atherogenesis?
formation of fatty deposits in arteries
128
What is atherothrombosis?
Blood clot within artery
129
What percentage narrowing ensures limited blood flow?
70%
130
What can atherothrombosis cause?
Angina
131
What can the inflammatory process driving the atherosclerosis lead to?
Thinning of capillary making it erode or rupture.
| This leads to atherothrombosis since body wants to heal the rupture and form a thrombus.
132
What happens to a platelet when its activated?
Its shape changes. It changes from smooth discoid to spiculated (spikes/pointed) and pseudopodial.
The surface area increases
There is increased possibility of cell interactions because number of receptors increases.
There is increased affinity of receptor for fibrinogen (needed for platelet aggregation),
133
What receptors are on the surface of a platelet?
Glycoprotein IIb/IIa receptors
| 50,000-100,000 copies on resting platelet
134
Platelet action after atherosclerotic plaque rupture
Platelets adhere to damaged vessel wall. The collagen receptors bind to subendothelial collagen which is exposed. GPIIb/IIIa receptors on platelets bind to von Willebrand factor which is attached to collagen . The α2β1 receptor binds to collagen which slows the platelets down. Platelets come to a half and GPVI binds to collagen and activates platelets. Platelets release chemical which recruit other platelets and cause aggregation.
135
What is platelet adhesion?
A platelet spreading out on a collagen-coated surface
136
Platelet activation mechanisms
See M's notes
137
COX-1 (Cyclooxygenase-1) enzyme
Mediates GI mucosal integrity
COX-1 --> Prostaglandin H2 --> Thromboxane A2
Thromboxane A2 released when platelet binds to collagen and mediates aggregation as well as stimulating contraction of the artery. Low doses of aspirin INHIBIT COX-1 pathway production of T-A2 which is good during/before heart attacks to prevent thrombus.
138
COX-2 (Cyclooxygenase-2) enzyme
Mediates inflammation
Mediates prostacyclin production, which inhibits platelet aggregation and affects renal function. keeps blood flowing.
COX-2/COX-1 => Prostaglandin H2 => Prostacyclin
139
Aspirin + COX
Low dose inhibits COX-1
| High dose inhibits both COX-1 and COX-2.
140
What are the ADP receptors on platelets?
P2Y1
| P2Y12
141
P2Y1 receptor
Link to Gq protein activating phospholipase C, mobilising calcium and initiates platelet activation
142
P2Y12 receptor
Linked to Gi protein which inhibits formation of cAMP, allowing for amplification of platelet activation.
143
What do the P2Y1 and P2Y12 pathways lead to?
The production of dense granules which get shunted to the surface of activated platelets and released. One of the content of these granules is ADP, which further activates the pathways greating a positive feedback loop. When GPIIb/IIIa binds to fibrnogen this causes further amplification.
144
What is an example of a receptor activated by Thrombin?
PAR-1
145
Platelet procoagulant activity mediated by changes to the membrane lipid bilayer
1) Platelet activation causes a change in the lipid bilayer.
2) Activation of PAR-1 receptor due to thrombin causes the release of calcium ions from intracellular stores.
3) This inhibits translocase and scramblase enzymes, causing amino-phospholipids to flip and express themselves onto the outer platelet membrane.
4) This exposure allows prothrombinase to bind to the membrane and convert prothrombin into thrombin.
146
What is the function of the fibrinolytic system?
Ensures a balance in the coagulation cycle
| It is a system to break down the fibrinogen strands and dissolve the clot.
147
Fibronlytic system
Healthy endothelial cells release tPa (tissue plasminogen activator) which converts plasminogen into plasmin.
Plasmin breaks down fibrin into fibrin degradation products, and dissolvs the clot.
148
Inhibitors of the Fibronlytic system
PAI-1 blocks tPa
| Antiplasmin blocks plasmin
149
α granules
- contribute to thrombotic response because they contain coagulation factors
- drive inflammatory response due to their inflammatory mediators (wound healing)
- contain P-selectin allowing platelets to bind to WBC
150
Platelet summary
See M notes page 28-29
151
Where can the apex beat be heard?
Left 5th intercostal space
| Mid-clavicular line
152
Which chambers of the heart is anterior?
Mainly right ventricle
153
Which chambers of the heart are posterior?
Mainly left atrium and pulmonary veins
154
2 layers of the pericardium
Visceral
| Parietal
155
What is a cardiac tamponade?
Restricts the rapid collection of pericardial fluid and impairs filling
156
What does pleural reflection allow?
Drainage of pericardial fluid from the left of the xiphisternum
157
What attaches papillary muscles of the ventricle to atriventricular valves?
chordae tendinae
158
What is the function of the coronary sinus?
drains blood from the heart muscle into the right atrium
159
What separates the smooth and trabeculated portions of the right atrium?
Crista terminalis
160
What is the Fossa ovalis?
The remains of the foramen ovale which was patent in foetal life
161
Where do coronary muscle cells cross link and join?
Intercalated discs
162
From where do coronary arteries arise?
Aortic root sinuses
163
How many main coronary arteries are there?
two - left and right
164
What does the left main stem divide into?
Left anterior descending and circumflex branches
165
Where does the left anterior descending branch?
The anterior interventricular groove
166
What does the left anterior descending give off?
Septal and diagonal branches to the septum and left ventricular myocardium
167
Where does the circumflex run?
Left atrioventricular groove
168
What does the circumflex give off?
Obtuse marginal branches to the posterolateral left ventricular wall
169
In 10% of people what does the circumflex provide?
Posterior descending artery
170
Where does the right coronary artery run?
Right atrioventricular groove
171
What does the RCA supply?
The sinus node
Atrioventricular node
Branches to the anterior right ventricle wall
172
What does distal RCA branch into?
Posterolateral and posterior descending arteries
173
Where does the posterior descending artery run?
Inferior septum
| Left ventricle
174
Components of the Heart Conduction system
SA node
AV node
Bundle of His
Purkinje Fibres
175
What joins myocytes?
Intercalated discs (containing gap junctions and desmosomes)
176
Properties of myocytes
Branched tubular cell (strirated)
High mitochondrial density
Contains sarcromeres/myofibrils
177
Resting membrane potential of myocytes
Polarised
Negatively charged inside the cell (-90mV)
Unbalanced ion concentrations and active membrane pumps result in an external positive charge.
178
What does the pump in myocyte membrane do?
Na/K pump
3Na+ ions are transferred outside the cell and 2K+ transferred inside the cell maintaining the cell polarisation.
(Calcium also moves out with sodium).
179
What is the myocyte membrane permeable to?
Potassium ions.
| The diffusion of potassium out of the cell allows negative polarisation inside the cell.
180
Myocardial action potential
Spread from one cell to another through gap junctions (connexins) and this activates other myocytes.
AV node and Purkinje fibres have similar action potentials but at a slower rate, therefore usually stimulated by potentials spreading from the AV node.
181
Summary of action potential process (6)
```
Depolarisation
Repolarisation
Propagation
Excitation-contraction coupling
Automaticity related to pacemaker AP
Refractory period
```
182
Depolarisation
Rapid influx of sodium ions prolonged by influx of calcium ions
183
Repolarisation
potassium diffuses out of membrane
184
Propagation
Positive sodium ions depolarise adjacent cells and gap junctions
185
Excitation-contraction coupling
Release of calcium from T-tubules and sarcoplasmic reticulum.
186
Automacity related to pacemaker action potential
Slow sodium ion influx
187
Refractory period
Fast sodium ion and slow calcium ion channels close.
188
Phase numbers and their change in potential
0 = Rapid depolarisation (na+ inflow)
1 = Partial repolarisation
(K+ outflow/Na+ inflow stops)
2 = Plateau
(slow inflow of Ca2+)
3 = Repolarisation
(K+ outflow/inflow of Ca2+ stops)
4 = Resting potential
(K+ outflow only)
189
Refractory period (two kinds)
ABSOLUTE refractory period = inactivation of the sodium channels which close and do not open.
RELATIVE refractory period = sodium channels start to activate gradually. If a lot of channels reactivate another action potential can be stimulated.
190
Automaticity - pacemaker cells
Pacemaker cells have no true resting membrane potential and constantly drift towards the value of the action potential.
191
2 kinds of autonomic control
Sympathetic stimulation
| Parasympathetic stimulation
192
What is sympathetic stimulation controlled by?
Adrenaline and noradrenaline and type 1 beta adrenoreceptors.
Increases adenyl cyclase => increases cAMP (Activating sodium and calcium channels and so allowing the the threshold to be reached sooner)
193
What does increased sympathetic stimulation result in?
Increased heart rate
Increased force of contraction
Large increase in cardiac output by up to 200%
194
What does decreased sympathetic stimulation result in?
Decrease in heart rate and decrease in cardiac output by 30%.
Blocking type 1 beta adrenareceptora (beta-blockers).
195
What is parasympathetic stimulation controlled by?
Acetylcholine
| M2 receptors - inhibit adenyl cyclase => reduced cAMP (less sodium and calcium ions, activation of potassium ions)
196
What does increased parasympathetic stimulation result in?
Decreased heart rate
Decreased cardiac output ~50%
Decreased force of contraction
197
What does decreased parasympathetic stimulation result in?
Increased heart rate
198
Active Potential Propogation - why is it needed?
Effective cell-cell communication is critical for rapid, uniform conduction of cardiac action potentials because it allows the heart to contract co-ordinately.
199
How does active propogation happen?
There is a free flow of positive sodium ions between cardiomyocytes through gap junctions within the intercalated discs. This then allows neighbouring cells to reach their threshold and activate their own voltage gated sodium channels. Cannot bounce backwards due to refractory period.
200
Where is sinoatrial node located?
Posterior wall of Right Atrium
201
Conduction pathway SAN
Wave front conducted through right atrium by backward bundles to the left atrium and down to the atrioventricular node.
202
What does the SAN determine?
It is the primary pacemaker and normally determines the heart rate the heart beats.
203
Resting membrane potential of SAN.
| What is the AP driven by?
negative
-55mV to -60mV
AP driven by slow Ca2+ channels because of slow Na+ inflow
204
Atrioventricular node
Transmits cardiac impulse between atria and ventricles.
| Delays the impulse, allowing the atria to empty blood into ventricles.
205
Adaptations of AV node for its function
Less gap junctions - sodium ions move less quickly
Smaller fibres than atrial fibres = longer transmission
206
His-Purkinje System
Conduction down bundle of His to the left and right Purkinje fibres.
Spread from endocardium to pericardium.
207
Speed of conduction in His-Purkinje system - and why? How is it adapted to suit this speed?
Rapid!
This allows coordinated ventricular contraction from apex base.
Very large fibres and high permeability at gap junction.
208
Where in the heart can pacemaker cells be found?
SAN
AVN
HP system
209
Hierarchy of pacemakers
A slower pacemaker is blocked by a faster one
210
Myocardial Action Potential vs Skeletal Action potential
Key difference = the plateau phase.
| Allows the heart to fill.
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Mycardial contraction vs skeletal contraction
M is 15x longer
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Excitation Contraction Coupling
| purpose, which phase, what is it dependent on, what is the process
This stage is how an electrical impulse is translated into cardiac contraction. It's dependent on calcium ions and happens during Phase 2 plateau.
Inward calcium current increases intracellular calcium concnetration, which activates receptors on sarcoplasmic reticulum leading to more release of calcium ions from the sarcoplasmic reticulum. Calcium ions bind to troponin C on actin filaments. This induces a conformational change exposing the actin-myosin binding site. Actin binds to myosin and cardiac contraction occurs.
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What does an ECG show?
Changes in voltage over time (not action potential)
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Baseline of ECG
Isoelectric point
| = no net current flow in direction of lead
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Positive deflection (up) from baseline
Net current flow towards lead
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Negative deflection (down) from baseline
Net current flow away from lead
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1 big square ECG
5mmx5mm
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1 small square ECG
1mmx1mm
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Typical speed and voltage settings ECG
```
Speed = 25mm/sec
Voltage = 10mm/mV
```
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Big/small squares (horizontal) and speed
5 big squares = 1 second
1 big square OR 5 small squares = 0.2 seconds
1 small square = 0.04 seconds
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Big/small squares (vertical) and voltage
2 big squares = 1mV
| 1 big square = 0.5mV
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What is an R-R interval
Time between beats/QRS complexes on ECG
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P wave
atrial depolarization
| less than 3 small squares
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PR interval
Slow conduction between AV node and His-Purkinje system
3-5 small squares
120-200ms
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QRS complex
Ventricular depolarisation
up to 120 ms
3 small squares
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ST segment
The interval between depolarisation and repolarisation
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T wave
Ventricular repolarisation
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QT interval
Time of depolarisation and repolarisation
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What causes QT interval to vary
heart rate
| faster heart rate = shorter QT
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Why can QT interval be prolonged? What are the values for prolonged QT in both men and women
Ischaemia, drugs, congenital issues
440 men
460 women
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How do you perform an ECG?
Electrodes are placed on the skin, 6 chest leads and 4 limb leads.
V1: 4th intercostal space right side septum
V2: 4th intercostal space left sternal edge
V4: 5th intercostal space on midclavicular line
V3: half way between LSE and MCL leads
V6: 5th intercostal space on midaxillary line
V5: halfway between MAL and MCL
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12 Lead ECG
```
aVF => +- 90°
III => -60°, +120°
aVL => -30°, +150°
I => 0°, +180°
aVR => +30°, -150°
II => +60°, -120°
```
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Lateral Leads
I
avL
V5
V6
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Septal leads
V1
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Anterior leads
V2, V3, V4
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Inferior leads
II
III
avF
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What can be deduced about electrical impulses from viewing a single electrode?
Electrical impulse is only briefly in the direction of electrode before it changes direction.
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Wat can you say about electrical impulse for atria in comparison to ventricles
The impulse for the atria is smaller since atria are smaller and have less myocytes.
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Abnormalities in P wave - tall peaked P wave
right atrial enlargement
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Abnormalities in P wave - Bifid P wave
left atrial enlargement
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Abnormalities in P wave- inverted P waves
non sinus origin (junctional or ecptopic atrial)
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Abnormalities in QRS complex - broad complex
Ventricular origin (e.g. ventricular tachycardia)
Hyperkalemia (too much potassium)
Ventricular pacing
Left and right bundle branch block
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Abnormalities in QRS complex - high voltage
ventricular hypertrophy (thickening of wall)
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ST segment abnormalities: ST segment depression causes
```
Digoxin toxicity
Hypokalaemia
Ventricular hypertrophy
Myocardial infarction
Pulmonary embolism
Raised intracranial pressure
```
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Dextrocardia
Multiple -ve P waves
Low voltage V3-V6 with no progression
Can record right sided chest leads, which mirror the normal leads
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Main components of the myocardium
Contractile tissue
Connective tissue
Fibrous frame
Specialised conduction system
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What does myocardial metabolism rely on?
Relies on free fatty acids during aerobic metabolism (efficient energy production)
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Myocardial metabolism during hypoxia
During ypoxia, there is no FFA metabolism, thus anaerobic metabolism ensues. This relies on metabolising glucose anaerobically producing energy sufficient to maintain the survival or the affected muscle without contraction.
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Ultrastructure of the myocardial working cell: how are the contractile proteins arranged?
In a regular array of thick myosin and thin actin filaments (myofibrils)
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The sarcomere
The functional unit of the contracile apparatus. It is the region between a pair of Z-lines, containing two half I-bands and one A-band.
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The sarcoplasmic reticulum
A membrane network that surrounds the contractile proteins. It consists of the sarcotubular network at the centre of the sarcomere and the subsarcolemmal cisternae (T-tubules and sarcolemma) so that Ca2+ ions are always available.
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What lines the transverse tubule (T-tubule) system?
A membrane that is continuous with the sarcolemma, so that the lumen of the T-tubules carries the extracellular space towards the centre of the myocardial cell.
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Where is mitochondria found in myocardium
In between myofibrils.
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A-band
The region of the sarcomere occupied by the thick filaments (myosin)
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I-band
Occupied only by thin actin filaments that extend towards the centre of the sarcomere from the Z-lines. It also contains tropomyosin and troponins.
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What attaches atin filaments to the Z-lines?
Titin proteins, which provide elasticity.
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What happens when titin proteins are damaged?
Elongation of the muscle => heart failure.
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Summary of contraction mechanism
- Depolarisation of the cell membrane.
- Influx of Ca2+ inwards
- Ca2+ binds to troponin.
- Troponin changes shape and troponin-tropomyosin complex is lifted from the actin groove
- The actin-myosin binding site is exposed
- Actin moves closer to the centre of the sarcomere, allowing for myosin bridge to bind to actin and causes contraction
- Sliding of actin over myosin by ATP hydrolysis through the action of ATPase in the head of the myosin molecule. These heads form the cross bridges that interact with actin, after linkage between calcium and troponin, and deactivation of tropomyosin and TnI (changed troponin).
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Repolarisation muscle
Cells spend energy to removed Ca2+ from troponin, allowing it to inhibit actin-myosin interaction. The bridges are separated and actin is moved back. Muscle relaxes.
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Myosin structure
2 heavy chains (responsible for the dual heads)
4 light chains
The heads are perpendicular on the thick filament at rest, and bend towards the centre of the sarcomere during contraction.
Alpha and beta myosin.
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Actin structure and properties
Globular protein
Double-stranded macromolecular helix (G) - creates a groove where the myosin acts which is covered by the troponin-tropomyosin complex.
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Tropomyosin structure and properties
Elongated molecule, made of two helical peptide chains.
| It occupies each of the longitudinal grooves between the two actin strands.
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Troponin TnI
forms complex with tropomyosin to inhibit actin and myosin interaction
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Troponin TnT
binds troponin to tropomyosin
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Troponin TnC
high affinity calcium binding sites, signalling contraction
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Circulation in the heart
Superior + inferior Vena Cava bring deoxygenated blood to right atrium
Blood moved across tricuspid valve to right ventricle
Blood is squeezed out of right ventricle, through the pulmonary artery into the lungs across the pulmonary valve
Oxygenated blood comes back to the heart through the 4 pulmonary veins into the left atrium
Moved down into the left ventricle across the mitral valve
Left ventricle squeezes blood out the aorta across the aortic valve into systematic circulation.
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Cardiac cycle overview of stages
- Isovolumic contraction
- Ejection
- Isovolumic relaxation
- Rapid inflow
- Diastasis
- Atrial systole
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ECG and cardiac cycle
P - atrium depolarised; occurs before atrial contraction
QRS - ventricle depolarisaed; occurs just as ventricles begin to contract
T - repolarisation
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First heart sound
Closure of the mitral valve at the end of diastole + beginning of isovolumetric contraction
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Second heart sound
Closure of the aortic valve at the end of ventricle emptying and beginning of isovolumetric relaxation
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Ventricular pressure + LV Conctraction
During isovolumetric contraction the volume of the ventricle does not change, both the valves are closed. The ventricle changes shape as it squeezes. This raises the pressure to open the aortic valve.
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How much blood remains in ventricle after it contracts?
30%
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Ventricular pressure during left ventricle relaxation
At the start of relaxation and reduced ejection the aortic valve shuts. The ventricle wall continues to relax and lose pressure with 1/3 of normal volume. Rapid LA filling causes blood to passively move into ventricles down pressure gradient when mitral valve opens. During diastasis the pressure in ventricles starts rising and pressure in atrium and ventricle are equal. There is no movement of blood. Atrial booster is contraction of atrium to squeeze in extra blood.
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What is a 4th heart sound indicative of?
Stiff atria/heart failure
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Ventricular contraction - systole
| Steps
Wave of depolarisation arrives and opens the L-calcium tubule (on an ECG, this is the peak of R). Calcium ions arrive at the contractile proteins. Left ventricle pressure rises to above left atrial pressure. The mitral valve closes. Left ventricular pressure rises to above aortic pressure. Aortic valve opens and ejection starts.
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Ventricular relaxation - diastole
| STEPS
LVp peaks then decreases. The influence of phosphorylated phospholambdan; cytosolic calcium is taken up into the sarcoplasmic reticulum. This creates a phase of reduced ejection. Aortic flow is maintained by aortic distensibility. Aortic pressure exceeds LVp, aortic valve closes.
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Ventricular filling - steps
LAp is greater than LVp, mitral valve opens, rapid filling starts. Ventricular suction may also contribute to E filling.
Diastisis - LVp = LAp. Filling temporarily stops. Filling is renewed when atrial booster raises LAp creating a pressure gradient.
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Preload
Load present before left ventricle contraction has started; amount of stress in ventricle.
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Afterload
Load after the ventricle contracts.
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Contractility (inotropic state)
The state of the heart which enables it to increase its contraction velocity, to achieve higher pressure, where contractility is increased.
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Elasitcity
the myocardial ability to recover its normal shape after removal of systolic stress.
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Compliance
compliance = how easily a chamber of the heart or the lumen of a blood vessel expands when it is filled with a volume of blood
the relationship between the change in stress and the resultant strain.
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Diastolic distensibility
The pressure required to fill the ventricle to the same diastolic volume.
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The pressure-volume loop
contractility in the end-systolic pressure volume relationship, while compliance is reflected at the end diastolic pressure volume relationship.
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Pulmonary and bronchial circulation
Dual blood supply
Pulmonary circulation from right ventricle
Bronchial circulation takes 2% of left ventricle output.
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Pulmonary vs Systemic arteries: vessel wall
```
Pul. = thin
System = thick
```
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Pulmonary vs Systemic arteries: muscularization
```
Pulmonary = minor
Systematic = significant
```
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Pulmonary vs Systemic arteries: need for redistribution
```
Pulmonary = not in normal state
Systematic = yes
```
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mPAP
mean pulmonary arterial pressure
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PAWP
pulmonary arterial wedge pressure (estimate of LA pressure)
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mPAP - PAWP = ...
CO X Pulmonary vascular resistance
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What happens to mPAP and CO during exercise? Why is there a difference?
mPAP remains stable
CO increases signifiantly.
This occurs due to resistance falling by recruitment and distension of capillaries in response to increase pulmonary artery pressure.
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Hypoxaemia
low oxygen in blood
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Type 1 respiratory failure values of pO2 and pCO2
(O2) less than 8kPa
| (CO2) less than 6kPa
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Type 2 respiratory failure values of pO2 and pCO2
pO2 less than 8kPa
| CO2 more than 6kPa because with Type II there is a problem with removing CO2.
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Causes of hypoxaemia
Hypoventilation
Diffusion impairment across alveoli capillary membrane
Shunting (blood going through without ventilation)
Mismatch between ventilation and perfusion.
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Hypoventilation
```
(occurs during type II RF)
Failure to ventilate the alveoli.
Leads to muscle weakness.
Obesity.
Loss of respiratory drive.
Examples in motor neurone disease, kyphosis/scoliosis
```
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Diffusion impairment (hint: 3 types)
1. Gaseous diffusion - pulmonary oedema (fluid build up in alveoli). Pulmonary fibrosis increases thickness of lungs.
2. Blood diffusion - anaemia
3. Membrane diffusion - interstitial fibrosis
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V/Q = 1
Optimal gas exchange, occuring when regions of lung are ventilated in proportion to their perfusion.
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V/Q mismatch cases
Pulmonary embolism
Asthma
Pneumonia
Pulmonary oedema
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V/Q > 1
(Dead space)
Ventilation in excess of perfusion.
However, pulmonary blood is passing ventilated alveoli and PaO2 is normal.
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V/Q 0-1
Perfusion in excess of ventilation.
| increasing PAO2 will increase PaO2.
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V/Q = 0
shunt
Mixed venous blood entering the systemic circulation without being oxygenated vis passage through the lungs.
PaO2 falls.
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Physiological shunt
Bronchial arteries - blood not taking part on gas transfer
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Intracardiac shunt
Eisenmenger's syndrome
| Ventricular septum defect (VSD).
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Pulmonary shunt
Arterio-venous malformation (skipping the capillaries and so not oxygenating the blood).
Complete lobar collapse.
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Eisenmenger's syndrome
Baby will not be born blue, as oxygenated bloood in the left ventricle moves to the right ventricle and out of the pulmonary artery. However excess volume under high pressure in the pulmonary artery damages it, creating narrowing, increasing resistance and pressure. Blood then goes from RV to LV, and patients present with cyanosis (blueish discolouration of skin). Rasping murmur will be heard. Another symptom of R/L shunt is clubbing of the nails, and polycythaemia (excess red cells with secondary erythrocytosis).
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Hypoxic Pulmonary vasoconstriction
Local action of hypoxia on pulmonary artery wall. Weak response as little muscle. Aims to improve V/Q matching.
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Diseases of the pulmonary circulation
Pulmonary embolism
Pulmonary hypertrophy
Pulmonary arteriovenous malformations
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Pulmonary embolism
A large thrombus = can block the lungs centrally.
| A smaller clot is not as severe but causes infarction.
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How is a pulmonary embolism diagnosed?
CT scan
V/Q scan
Inhaling radioactive gas to see even ventilation.
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Virchow's Triad
3 things that make you more likely to have bloodclots; risk increases with the more of these you have.
1. Circulatory Stasis (blood not moving in the legs properly)
2. Endothelial injury
3. Hypercoagulable state (increased risk of bleeding thrombophilia (more likely to clot)).
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Pulmonary arterial hypertension progression
Normal pulmonary artery -> intermedia layer thickens.
The right ventricle increases in size
Left ventricle becomes smaller.
Increased pulmonary ventricular resistance.
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What does pulmonary arteriovenous malformation (shunt) cause
Hypoxaemia
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Blood pressure equation
BP = CO X Total peripheral resistance
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Pulse pressure equation
systolic - diastolic p
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Mean arterial pressure equation
Diastolic pressure + 1/3 pulse pressure
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Frank-Starling Mechanism.
Stroke volume increases as end-diastolic volume increases due to length-tension relationship of muscle. As the end-diastolic-volume increases, stretch increases and the force of contraction increases. Cardiac muscle at rest is not at is optiumum length.
↑VR = ↑EDV = ↑SV = ↑CO (even if HR constant)
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What factors effect blood volume
Renin-Angiotensin-Aldosterone system
ADH
Adrenals and kidneys
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How is blood pressure measured?
using a sphgmomanometer using bracial artery
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Control of pressure
```
Autoregulation
Local mediators
Humoral factors
Baroreceptors
Central neural control
```
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Myogenic autoregulation - what is it and what does it regulate?
Stretching of the arteriole.
| Regulates the constant flow despite perfusion pressure changes.
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Where is myogenic autoregulation excellent, moderate and poor?
```
Excellent = renal/cerebral/coronary
Moderate = skeletal muscle/splanchic
Poor = cutaneous (skin)
```
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Balancing intrinsic and extrinsic controls: brain &heart
Intrinsic control dominates to maintain bloodflow to vital organs
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Balancing intrinsic and extrinsic controls: skin
Blood flow is important in general vasoconstrictor response and also in responses to temperature (extrinsic) via hypothalamus.
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Balancing intrinsic and extrinsic controls: skeletal muscle
Dual effects: at rest, vasoconstrictor (Extrinsic) tone is dominant; upon exercise, intrinsic mechanisms predominate (Rapid release of blood into muscles)
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Local humoral factors (vasoconstrictors)
Endothelin- 1
| Internal blood pressure (myogenic contraction).
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Local humoral factors (vasodilators)
```
Hypoxia
Adenosine
Bradykinin
NO
Potassium ions
Carbon dioxide
[H+]
Tissue breakdown products
```
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What is the endothelium derived relaxing factor?
Nitric oxide, a potent vasodilator, which is produced by the endothelium.
L-Arginine is converted into NO by NO synthase.
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Prostacyclin
potent vasodilator
331
Endothelin
potent vasoconstrictor
332
Circulating (hormonal) factors - Vasoconstrictors
Epinephrine
Angiotensin II
Vasopressin
333
Circulating (hormonal) factors - Vasodilators
Epinephrine
| Atrial Natriuretic peptide (ANP)
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Baroreceptors
pressure receptors
335
Primary baroreceptors
Arterial
| => carotid sinus and aortic arch
336
Secondary baroreceptors
veins, myocardium, pulmonary vessels
337
What is baroreceptor firing rate proportional to?
MAP and PP, integrated in the medulla
338
How do arterial baroreceptors affect central control:
An increase in blood pressure leads to an increase in firing rate leading to an increase in parasympathetic nerve supply (?) and decrease in sympathetic nerve supply (?) leading to a decrease in cardiac outflow and total peripheral resistance and thus a decrease in blood pressure.
339
Arterial baroreceptors
Key role in short-term regulation of BP; minute to minute control, response to exercise, haemorrhage.
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What happens if arterial pressure deviates from the norm?
If arterial pressure deviates from the norm for a few days the baroreceptors adapt or reset to new baselin pressure, for example in hypertension.
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Cardiopulmonary baroreceptors
Atria, ventricles, pulmonary artery
Stimulation leads to a decrease in vasoconstriction. Also leads to decrease in angiotensin, aldosterone and ADH/vasopressin, leading to fluid loss.
342
Main neural influence on medulla
```
Baroreceptors
Chemoreceptors
Hypothalamus
Cerebral cortex
Skin
Changes in blood [O2] and [CO2]
```
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Which higher centers do CV reflexes require
hypothalamus
| pons
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Effect of stimulation of anterior hypothalamus on CVS
Decrease in blood pressure
| Decrease in heart rate
345
Effect of stimulation of posterolateral hypothalamus on CVS
Increase in BP and HR
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How can the cerebral cortex affect blood flow and pressure?
Stimulation of CC usually increases vasoconstriction, but emotion can increase vasdilation and depressor responses e.g. blushing or fainting. Effects mediated via medula, but some also directly.
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Central chemoreceptors
Chemosensitive regions in the medulla. An increase in PaCO2 leads to vasoconstriction, an increase in peripheral resistance and an increase in blood pressure.
A decrease in PaCO2 leads to a decrease in medullary tonic acitivty and a decrease in BP.
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Fainting (neuro-cardiogenic syncope) symptoms, physiology, signs and treatment
Nausea, air hunger, sweating, light headed.
Fall in HR and venous pooling
Collapse due to decrease in CO.
HR falls, CO falls, BP falls, perfusion to brain reduced.
Treatment = lay supine and elevate limbs to increase VR.
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Blood loss + homeostasis
Perfusion to brain must be maintained so local vasoconstriction. Cardiac output and blood pressure is maintained by increasing the heart rate.
Increase in sympathetic outflow.
Widespread cutaneous vasoconstriction (skin).
Eventually, the body goes into 'shock' i.e. BP down, pulse up, organ hypoperfusion and death.
Treatment: rapid volume replacement
