Download Cardiovascular System

Cardiovascular System
10 January 2012
14:02
Guide for use of these notes
Definitions
First of all thank you for choosing to download these notes to study from I hope you
find them useful, please feel free to email me if you have any problems with the
notes or if you notice any errors. I don't promise to respond to all emails but I'll do
my best.
Afterload- Weight not apparent to muscle in resting state, only encountered
upon contraction of the muscle.
For the cardiovascular notes I used "Vander's physiology" and "Systems of the BodyCardiovascular System"
Cardiac afterload- The afterload on the heart is the load against which the left
ventricle ejects the blood after the opening of the aortic valve.
I organise my notes so that you should read the learning objectives on the left then
proceed down the right hand side for a few learning objectives and then cross back
over to the left and continue like that.
Calcium transient is the rise and fall of calcium during contraction.
Anything in this highlighted green is a definition or explains basically something's
function.
Text highlighted in yellow or with a star is what I would deem important and key to
your information.
Italics and bold just help to make certain terms stand out.
The notes are a bit quirky but I hope you like them and find some of the memory
aides strange enough so that they stick in your head.
I provide them to you in OneNote format as that is how I created them, they can be
saved as PDF but the formatting is not as nice. The one caveat with this is that these
notes are freely copy able and editable. I would prefer if you didn't copy and paste
my notes into your own but used them as a reference or preferably instead
embellished these already existing notes by adding to them.
Good luck with first year
Stuart Taylor
Stuart's Cardiovascular System Page 1
Frank-Starling Relation- Increased diastolic fibre length increases ventricular
contraction. Think preload.
Law of Laplace- When the pressure within a cylinder is held constant, the
tension on its walls increases with increasing radius.
Mean frontal plane of the ventricles- Mean direction of depolarisation is to
bottom right- due to needing more current to polarises greater size of wall of
left ventricle.
Preload- The weight acting on a muscle that stretches it before it is stimulated
to contract.
Stroke Volume- In cardiovascular physiology, stroke volume (SV) is the volume
of blood pumped from one ventricle of the heart with each beat.
Anatomy of the heart and circulation
17 January 2012
14:02
Learning Objectives
Identify the pericardium in the cadaver and describe its organisation
Demonstrate the four chambers of the heart
List the vessels that enter or leave each of the chambers of the heart
Identify the origin of the brachiocephalic artery, the Subclavian arteries
and the carotid system of arteries in a cadaver
Describe the position and relations of the aortic arch and descending
aorta
Explain how blood returns from the head and neck to the heart
Identify the superior vena cava in a cadaver
Outline the coronary circulation and be able to identify the main coronary
arteries and cardiac veins
Identify and label the heart valves and their locations, and state the
structural similarities and differences
Explain how blood leaving the heart reaches (a) head and neck, (b) lungs,
(c) thoracic and abdominal cavities
Describe the components of the conduction system
Identify the origin of the brachiocephalic artery, the subclavian arteries
and the carotid system of arteries in a cadaver
Identify the pericardium in the cadaver and describe its organisation
• The pericardium is located within the Inferior Mediastinum- the cavity that is
between the two pleural cavities. The heart is contained within pericardium
which is a fibrous sac and is stuck to the diaphragm and therefore moves during
breathing.
• Mesothelial cells line the inner pericardium.
Two layers of pericardium:
• Fibrous pericardium that stops expansion.
• Serous- Has some fluid with it. Two layers itself
i. Parietal- lines fibrous
ii. Visceral- adheres to heart.
Demonstrate the four chambers of the heart
List the vessels that enter or leave each of the chambers of the heart
Systemic circulation is to the body
Pulmonary circulation is to the lungs
Pulmonary trunk forms T shape due to vessels having to go to both lungs.
Arch travels leftwards and backwards
RA= Vena cava
RV= Pulmonary artery
LA= Pulmonary vein
LV= Aorta
• The brachiocephalic trunk is an offshoot of the ascending aorta.
• In terms of blood supply there is a necessity for having 4 arteries in order to
supply both upper limbs and both sides of the brain.
• Anatomically only one brachiocephalic trunk is needed because the arteries are
going in the same general direction with the aorta.
• When referring to arteries or veins etc. the term common means that the blood
vessel is likely to divide.
Explain how blood returns from the head and neck to the heart
Identify the superior vena cava in a cadaver
Identify and label the heart valves and their locations, and state the
structural similarities and differences
• There are 2 brachiocephalic veins in comparison to the one brachiocephalic artery/trunk.
• The 2 brachiocephalic veins are formed from the subclavian vein and the jugular vein. These
join with the superior vena cava and enter the right atrium of the heart.
• There are 3 main types of valve within the human heart.
• These are:
1) The tricuspid valve on the RHS of the heart.
2) The mitral (bicuspid) on the LHS of the heart.
3) Semi-lunar valves which stop back flow of blood from vessels
leaving the heart.
• The first two valves are collectively known as the Atrio-Ventricular valves.
• On a side note the snapping shut of the aortic semi-lunar valve gives the second
sound of the heart beat.
• For better version of second heartbeat look herehttp://www.youtube.com/watch?v=gvLmrCXjUuU
• Good memory note for remembering which side is which is "Try before you buy"
as if you were looking at a diagram of the heart.
• Supraventricular crest is a muscular ridge that separates/ regulates the effects of
the tricuspid and pulmonary valves.
The supraventricular crest is a circular muscular ridge on the inner wall of
the right ventricle, separating its inflow and the outflow aspects (i.e. the
tricuspid and pulmonary valves. Source: Medcyclopaedia.
• Tricuspid valve has 3 cusps:
First. Anterior cusp
Second. Septal cusp
Third. Posterior cusp
• Mitral valve has 2 cusps:
Stuart's Cardiovascular System Page 2
Outline the coronary circulation and be able to identify the main coronary arteries
and cardiac veins
First. Anterior cusp
Second. Septal cusp
Third. Posterior cusp
• Mitral valve has 2 cusps:
Outline the coronary circulation and be able to identify the main coronary arteries
and cardiac veins
First. Anterior cusp
Second. Posterior cusp
• Posterior interventricular is given off by right coronary artery.
• Anterior interventricular is given off by left coronary artery.
• Tendon like structure are called (Chordae tendineae) these prevent the valve
from prolapsing under the pressure of the back flow of blood.
• An analogy the lecturer used was to think of these cords like the cords of a
parachute- by pulling down on them you stop the parachute tarpaulin from
inverting due to air resistance.
LHS of Heart
The Coronary sinus is a vein that drains the heart.
Describe the components of the conduction system
• Sinoatrial node this is the pacemaker of the heart.
• Atrioventricular node- Collection of contracting myocytes
• Coronary arteries are supplied by blood that comes out of the aorta.
• The blood that collects in the semi-lunar cusps is delivered to the coronary
arteries at diastole upon back flow of blood.
• Out of the three semilunar cusps 2 supply coronary arteries and the posterior is a
non-coronary sinus.
• The sinuses on the RHS of the heart are the right, anterior and left cusps.
• Coronary veins drain into right atrium
Qu. 1: In the normal adult what is the name of the oval depression in the
right atrium where the septum is thin?
Foramen ovale
√ Oval fossa
Ligamentum arteriosum
Supraventricular crest
Moderator band
√ Mark = 1 (conf=1 )
Best Option: Oval fossa
Foramen ovale is the term used in the foetus.
Lecture: Chambers,valves, conduction system and coronary circulation
Pasted from <https://www.ucl.ac.uk/lapt/laptlite/sys/run.htm?icl08_cvs1?f=clear?i=icl1?k=1?u=_st1511?i=Imperial>
• 3 nodal tracts going from the SAN to the AVN which are:
○ Anterior nodal tract
○ Middle nodal tract
○ Posterior nodal tract
Qu. 7: What is meant by the term 'right coronary dominance'?
X Right coronary artery supplies more blood than left coronary artery to
heart
Right coronary artery receives a greater supply from posterior
descending coronary artery
Stuart's Cardiovascular System Page 3
Qu. 6: Which of the following components of a blood vessel contains a
small network of blood vessels called the vasa vasorum?
X Right coronary artery supplies more blood than left coronary artery to
heart
Right coronary artery receives a greater supply from posterior
descending coronary artery
Right coronary artery supplies posterior descending coronary
artery
Right coronary artery does NOT supply posterior descending
coronary artery
Right coronary artery branches more than left system
X Mark = -2 (conf=2 )
Best Option: Right coronary artery supplies posterior descending coronary
artery
In 85% of cases, the right coronary artery (RCA) is a dominant vessel and
supplies the posterior descending branch that travels in the posterior
interventricular groove.
Source: cardiologysite.com/html/rca/.html. A.S.M Systems, 2007.
Qu. 6: Which of the following components of a blood vessel contains a
small network of blood vessels called the vasa vasorum?
√ Adventitia
Elastic lamina
Media
Intima
Valves
√ Mark = 1 (conf=1 )
Best Option: Adventitia
The adventitia is the outer layer of connective tissue and nerve fibres that
contains a small network of vessels called 'vasa vasorum'.
Elastic lamina= layers of elastic fibres in vessel walls - internal layer below
intima, external layer between adventitia and media.
Media= smooth muscle (strength) and muscle fibres (elasticity).
Intima= endothelial cells and connective tissue.
Pasted from <https://www.ucl.ac.uk/lapt/laptlite/sys/run.htm?icl08_cvs1?f=clear?i=icl1?k=1?u=_st1511?i=Imperial>
Pasted from <https://www.ucl.ac.uk/lapt/laptlite/sys/run.htm?icl08_cvs1?f=clear?i=icl1?k=1?u=_st1511?i=Imperial>
Stuart's Cardiovascular System Page 4
Mechanical Action of Heart
25 January 2012
10:07
Learning Objectives
Explain how calcium influences the heartbeat
List the sequence of events from excitation that bring about contraction
then relaxation of a ventricular cell
Use a graph to compare the length-tension relationships for cardiac and
skeletal muscle
Explain the concepts of preload and afterload
Explain how calcium influences the heartbeat
• Calcium transient is the rise and fall of calcium during contraction.
• Unlike in skeletal muscle external calcium is necessary for the contraction of the
myocytes and thus the production of the heartbeat.
• Reminder- Invagination in ventricular cells are t tubules. These carry surface
depolarisation deep in the cell. T tubule lies alongside each Z line of a myofibril.
• The sarcoplasmic reticulum is the organelle where the internal calcium is stored.
Despite being very important it is relatively small and only occupies about 4/5% of total
cell volume.
State Starling’s Law of the Heart
List the sequence of events from excitation that bring about contraction then
relaxation of a ventricular cell
Explain the mechanisms underlying Starling’s Law of the Heart
Excitation- Contraction Coupling of the heart
Describe the relationship between ventricular wall tension, chamber
radius, and chamber pressure (Law of Laplace)
Use a graph to compare the length-tension relationships for cardiac and
skeletal muscle
Ca
Cardiac Muscle:
Ca
Active force production
Isometric (no shortening)
contraction
Ca
Force
Passive force
A
B
C
Muscle length
Force transducer doesn’t allow shortening of the muscle
1. The presence of an action potential that passes down the t-tubule causes an increase in
the permeability of L-type (long lasting) Calcium channels.
 These calcium channels are in fact modified versions of the dihydropyridine
receptors that are required for excitation-contraction coupling in skeletal
muscle.
2. As the concentration of calcium is higher outside a cell calcium floods in.
3. Calcium then either:
○ Causes the release of further calcium from the Ryanodine receptors which are
calcium channels of the Sarcoplasmic Reticulum. This stage is known as Calcium
induced, calcium release (CI, CR)
○ Or binds straight to the myofibrils (Troponin C)
4. The next stage involves the removal of calcium and its transport back to the SR for
storage. This is done by the enzyme Ca ATPase. The muscle will now relax.
5. In order to maintain calcium balance, calcium that entered at the start must be
removed. This is performed by a Na/Ca Antiporter (Exchanger) whereby the influx of
sodium with its concentration gradient allows the efflux of calcium against its own.
• Inotropic effect/noradrenaline will increase the length calcium channels remain open.
Peculiarities of Calcium and Neuromuscular contraction:
• From the above description it seems obvious that an increased calcium concentration
intracellular should increase force of contraction. This is true see below:
• Cardiac muscle is more resistant to stretch and less compliant than skeletal muscle.
This is because of the differing properties of extracellular matrix and cytoskeleton.
• Furthermore on a physiological basis there is not enough blood supply to the heart to
allow prolonged stretching and furthermore it is limited anatomically by the
surrounding pericardium.
• Only the ascending limb of the relation is important for cardiac muscle i.e. 0-100%
muscle length.
Explain the concepts of preload and afterload
• The heart uses two forms of contraction. The first is isometric- this is where a force is
produced without muscle fibers actually shortening. Isotonic is where fibers actually
shorten. Refer to Mechanical Action of the Heart 2 for more detail.
• Preload- The weight acting on a muscle that stretches it before it is stimulated to
contract.
• Afterload- Weight not apparent to muscle in resting state, only encountered upon
contraction of the muscle.
Stuart's Cardiovascular System Page 5
• And likewise in cardiac muscle with extracellular calcium concentration- But its not.
• Extracellular calcium is not only used in muscular contractions but also in the
propagation of action potentials. Calcium affects the membranes permeability to
sodium and a low calcium ECF concentration causes an influx of sodium bringing the
membrane close to the threshold. Thus low ECF (hypocalcaemia) causes
neuromuscular hyperexcitability.
• One has to understand that we are talking about the effects of 2 different calcium
pools, one intracellular and the other extracellular.
Reference- Human Physiology by Lauralee Sherwood
State Starling’s Law of the Heart
• Frank-Starling Relation- Increased diastolic fibre length increases ventricular contraction.
• Ventricles pump greater stroke volume so that, at equilibrium, cardiac output exactly
balances the augmented venous return.
• Think!- If blood kept coming into the heart but the ventricles didn't expel the same
amount then things would fudge up and become unbalanced.
Explain the mechanisms underlying Starling’s Law of the Heart
• There are two main mechanisms that influence this relationship
1) Number of myofilament cross bridges that can form.
2) Changes in myofilament sensitivity to Ca.
Cross Bridges
Further graphs outlining the concept of pre and afterload
Isometric (no shortening) contraction
Force
Preload (stretch)
Isotonic (shortening) contraction
Calcium
Larger preload
• Calcium binds to the thin filament protein troponin C.
• At longer sarcomere lengths the affinity of troponin C is increased with regards to calcium
which means that less is required to achieve the same amount of force.
Small preload
Velocity of
shortening
Shortening
Afterload
Explanation- At shorter lengths than optimal the actin filaments overlap on themselves so
reducing the number of myosin cross bridges that can be made.
Afterload
In vivo correlates of preload and afterload:
Preload
• The filling of the ventricles during diastole stretches the ventricular walls- The level
of stretch is the determiner of the preload on the ventricles before blood
expulsion.
• Therefore preload is dependent upon the venous return to the heart.
• Measures of preload relate to these previous conceptions such that end-diastolic
volume, end diastolic pressure and right atrial pressure are all measures of
preload
Afterload
• The afterload on the heart is the load against which the left ventricle ejects the
blood after the opening of the aortic valve.
• Diastolic arterial blood pressure is the measure of the afterload.
• An increase in afterload decreases the amount of the isotonic shortening and
velocity of shortening.
• Hypertension increases afterload and as a result decreases the amount of isotonic
shortening.
Qu. 1: Which of the following structures is not involved in the movement of
Ca2+ into cytosol during contraction of cardiac muscle?
Describe the relationship between ventricular wall tension, chamber radius, and
chamber pressure (Law of Laplace)
• Stroke work- The work done by the heart to eject blood under pressure into the aorta
and pulmonary artery
• Stroke work= Stroke Volume x Pressure at which blood is ejected.
○ Preload and after load greatly influence SV
○ Structure greatly influence pressure
• Law of Laplace- When the pressure within a cylinder is held constant, the tension on its
walls increases with increasing radius.
Ryanodine receptors
Na-Ca exchanger
L-type Ca2+ channels
Sarcoplasmic reticulum
√ Na+-K+ ATPase
√ Mark = 2 (conf=2 )
Best Option: Na+-K+ ATPase
Ca2+ moves into the cytosol of cardiac muscle via various routes, including
release from the SR via ryanodine receptors, and also entry from the
extracellular space via L-type Ca2+ channels and via the Na+-Ca2+
exchanger.
Including wall thickness (h)
T=PR/h
Pasted from <https://www.ucl.ac.uk/lapt/laptlite/sys/run.htm?icl08_cvs1?f=clear?i=icl1?k=1?u=_st1511?i=Imperial>
• Radius of curvature of walls of LV is less than that of RV allowing LV to generate high
Stuart's Cardiovascular System Page 6
• Radius of curvature of walls of LV is less than that of RV allowing LV to generate high
pressures with similar wall stress.
Qu. 6: Which of the mechanisms does NOT contribute to the FrankStarling relationship (force of contraction is dependent on diastolic volume?
Force depends on the number of crossbridges binding myosin to
actin
Force depends on the Ca2+ sensitivity of troponin C
√ Force depends on the concentration of ATP around the
myofilaments
Force depends on the overlap between the myofilaments
Force depends on the Ca2+ affinity of troponin C
√ Mark = 3 (conf=3 )
Best Option: Force depends on the concentration of ATP around the
myofilaments
The Frank-Starling relationship is due to force being dependent upon 1) the
number crossbridges that interact between the overlapping myofilaments,
and 2) changes in Ca2+ sensitivity of the myofilaments, which is at least
partly due to alterations to the affinity of troponin C for Ca2+. Although
presence of ATP is necessary for the crossbridge cycle to occur, it is not a
part of the Frank-S
Pasted from <https://www.ucl.ac.uk/lapt/laptlite/sys/run.htm?icl08_cvs1?f=clear?i=icl1?k=1?u=_st1511?i=Imperial>
Stuart's Cardiovascular System Page 7
• Failing hearts often become dilated increasing radius and thus decreasing pressure
generation and increases wall stress.
Electrical Action of the Heart
27 January 2012
14:01
Page 364 Vander's Human Physiology
Learning Objectives
Describe the structure of a typical cardiac ventricular myocyte.
Describe the structure of a typical cardiac ventricular myocyte.
Describe the main structures of the human heart.
• Cardiac myocytes are about 50-100microns long.
• Attach to each other as end to end junctions known as intercalated discs.
• These discs have gap junctions- which allow action potential spread (syncytium) due
to low resistance.
Briefly describe the pathways of the heart that subserve the normal
orderly passage of electrical activity through it.
Sketch an intracellular action potential for a) a sino-atrial node cell b) an
atrial cell c) a ventricular cell.
Describe the main structures of the human heart.
Conduction System
• Sinoatrial node- strip of modified muscle tissue 20x4 mm in size located close to
Explain why the ventricular action potential has a long duration and
relate this to the function of the ventricles.
State that the sino-atrial (SA) node is the normal pacemaker and explain
why and how this is so.
Describe how activity in the SA node spreads to both atria.
where the Vena Cavae empties.
• Atrioventricular node- Bridges fibrous ring of atria and ventricles which is non
conducting.
• Bundle of His- Bundle of rapidly conducting muscle fibres- away from AV node into
the septum.
• Bundle Branches- Left bundle branch runs down left side of the septum.
• Purkinje Fibres- Endocardium- penetrate into ventricular muscle wall.
Explain why transmission of electrical activity from the atria to the
ventricles normally only occurs at the atrio-ventricular (A-V) node.
• The objective of the conduction system and in particular the Purkinje fibres is that the
contraction of the ventricles needs to be simultaneous in order to generate a large
pressure and force the blood out.
Describe how electrical activity is transmitted to all parts of the
ventricles through the Bundle of His and the Purkinje fibres.
• Interestingly the heart can beat outside of the body- remove and profuse it with a
certain solution it will beat. Different to skeletal muscle where this wouldn't happen.
Describe the ECG waveforms using the conventional PQRST
nomenclature, and state the electrical events that each represents.
Sketch an intracellular action potential for a) a sino-atrial node cell b)
an atrial cell c) a ventricular cell.
Sino Atrial Node
• In depth coverage of ion channels is covered in sino-atrial node learning
objective.
• Sympathetic nervous system causes slope of pre-potential to increase which
results in it being quicker and easy to establish an action potential and thus the
heart beat will be fast.
• The sympathetic nervous system uses noradrenaline.
• Parasympathetic- Vagal nerve- acetylcholine
Briefly describe the pathways of the heart that subserve the normal orderly
passage of electrical activity through it.
1. Atrial depolarisation occurs which is initiated by the sino-atrial node.
2. Depolarisation then reaches atrioventricular node which propagates the action
potential down the Bundle of His, bundle branches and finally to the purkinje fibres.
3. Purkinje fibres causes the ventricles to contract simultaneously.
State that the sino-atrial (SA) node is the normal pacemaker and explain why
and how this is so.
• The sino-atrial node is known as the pacemaker and determines how fast the heart
beats. This is because its depolarization initiates the depolarization of all other
myocytes.
• As opposed to typical cardiac myocytes SAN cells do not have a steady resting
membrane potential and instead undergo a slow depolarization known as a
pacemaker potential.
Explanation of SA Nodal Cell Action Potential:
+ 20 mV
1. Firstly K channels close so that membrane potential will not decrease further.
2. Next Na enters via F-type channels. These are so called because they have "funny"
gating behaviour as they open whilst negative.
3. Transient (T-Type) Ca channels then open to further boost towards the pacemaker
potential.
4. Once this is achieved L-type Ca channels open and the action potential is propagated.
Potential
(mV)
Threshold
- 50 mV
Pre-potential
Time
Atrial Cells
• Vaguely similar in shape to SAN cells however there is no pre potential and the
resting membrane potential is a lot lower at around -90mv.
+20mV
• The pacemaker currents within the SAN cells brings them to threshold much quicker
than AVN cells which is why they act as the pacemaker.
• If the AV node becomes dysfunctional then the ventricles will stop beating, this is a
condition known as heart block and has a characteristic change in an ECG.
• The reason why this is not fatal is because AV node cells take over pacemaker
function from SAN. Although the AV beats at only 35-40 BPM it is enough to stop us
from dying.
• The SA node is able to depolarise about 100 times a minute however this doesn't
happen due to moderate parasympathetic stimulation and the action of hormones.
• Junctional fibres introduce a delay of 90ms into depolarisation which means the atria
and ventricles do not contract simultaneously.
Describe how activity in the SA node spreads to both atria.
Potential
(mV)
• The action potential generated by the SA nodes spreads through the myocardium via
intercalated discs and gap junctions.
Explain why the ventricular action potential has a long duration and relate
this to the function of the ventricles.
- 100 mV
0
100
200
Time (ms)
300
400
Timing of ventricular action potential and isometric force
Ventricular cells
+20mV
Potential
(mV)
Stuart's Cardiovascular System Page 8
AP
scale
(mV)
force
scale
(N)
+20mV
Potential
(mV)
AP
scale
(mV)
force
scale
(N)
- 100 mV
0
100
200
Time (ms)
300
400
• Same resting membrane potential as atrial cells.
• However the duration of the repolarization phase is much longer at 215ms in
comparison to about 100ms.
• This longer duration results in a plateau phase which is caused by the inwards
movement of calcium ions, once the membrane potential reaches -35mv and this
delays the speed with which the membrane can become more negative.
AV Node cell
0
• Like ventricular but with pre potential.
Explain why transmission of electrical activity from the atria to the
ventricles normally only occurs at the atrio-ventricular (A-V) node.
• Apart from the AV node the atria and ventricles are not electrically compatible
as there is a thick layer of non conducting connective tissue between them.
Thus it is entirely necessary that the action potential go through the node in
order to innervate the rest of the heart myocytes.
Describe the ECG waveforms using the conventional PQRST
nomenclature, and state the electrical events that each represents.
Potential
(mV)
Time in ms
Typical ECG Waveform
NOTE:
When a wave of depolarisation is moving TOWARDS the positive electrode it
causes an UPWARD deflection.
When it is moving AWAY from the positive electrode it causes a DOWNWARD
deflection.
P wave= Atrial depolarisation
QRS= Ventricular depolarisation
T= Ventricular repolarisation
Atrial repolarisation gets swamped by QRS
Stuart's Cardiovascular System Page 9
200
Time (ms)
• The long duration of the ventricular action potential is required to stop the
production of a fused tetanus in myocytes.
• This works as the long duration resulting in a long refractory period which means
another action potential cannot be generated.
• This results in a better mechanism for pumping.
Describe how electrical activity is transmitted to all parts of the
ventricles through the Bundle of His and the Purkinje fibres.
• The Bundle of His passes down the septum and the splits into a left and right
bundle branch which enter the walls of the ventricles.
• These then make contact with large diameter Purkinje fibers which go on to
innervate all of the cardiac myocytes. Not simultaneously but very close to, so
the overall contraction is like that of squeezing toothpaste from the bottom of a
tube.
Understanding the ECG
27 January 2012
15:08
Learning Objectives
Describe how the recordings of the six standard limb leads are obtained
from the four electrodes attached to the limbs
Explain briefly the principles underlying the concept of Einthoven's
Triangle
Describe how the recordings of the six pre-cordial (chest) leads are
obtained
Appreciate why the magnitude and direction of components of the ECG
vary from lead to lead
State how the information obtained from the chest leads is different from
that derived from the limb leads
Describe how the recordings of the six standard limb leads are obtained
from the four electrodes attached to the limbs
Attachment of electrodes
• The right foot is always used as a zero volt reference point.
• This leaves the two arms and the left foot for recording signals
Explain briefly the principles underlying the concept of Einthoven's Triangle
• Einthoven's triangle is a concept that allows us to think about the ECG in a
particular way.
• The heart lies in centre of an equilateral triangle formed by the two arms and the
left foot which allows us to determine the relative polarities and directions of the
leads.
Explain why the magnitude and direction of the components of the ECG
vary as the recording electrode is moved across the chest from V1 to V6
Know the normal physiological range of the mean frontal plane axis
Understand what is meant by the terms left and right axis deviation, and
how these conditions may occur
Recordings
Lead 1- This is from the Left Arm to the Right Arm. LA is the + electrode
Lead 2- This is from the Right Arm to Left Foot. LF is the + electrode
Lead 3- This from the Left Arm to the Left Foot. LF is the + electrode.
Location of Chest Electrodes * Self Added
Describe how the recordings of the six pre-cordial (chest) leads are obtained
Appreciate why the magnitude and direction of components of the ECG vary
from lead to lead
• The effects of a wave of depolarisation are detected as the potential difference
between two electrodes.
• When a wave of depolarisation is moving TOWARDS the positive electrode it causes
an UPWARD deflection.
• When a wave of depolarisation is moving AWAY from the positive electrode it
causes a DOWNWARD deflection.
•
•
•
•
For aV leads the letter on the end is where the lead ends.
So aVR lead ends on Right Arm.
aVL lead ends on Left Arm
aVF lead ends at Left Foot
State how the information obtained from the chest leads is different from
that derived from the limb leads
2
3
aVL
aVR aVF
MFPA 0 degree ++
1
+
-
+
-
0
MFPA 90 degree 0
+
+
-
-
++
• In case you forget here is a few tips to remember how to know whether its positive
negative etc.
○ First off determine degree of MFPA
○ If the lead you are looking at is in same direction to MFPA's big red arrow then
the reading will be a ++.
○ If the lead is in the opposite direction of MFPA it will be a -.
○ If the lead is perpendicular to the MFPA then the reading will be 0.
Note:
• The AVR lead is almost always negative if not, you have either attached the
electrodes wrong or there is some underlying pathology.
Explain why the magnitude and direction of the components of the
ECG vary as the recording electrode is moved across the chest from V1
to V6
• This learning objective can best be described via some trigonometry.
• Think of SoH CaH ToA and the lengths of the lines as a measure of signal
strength
Stuart's Cardiovascular System Page 10
strength
Know the normal physiological range of the mean frontal plane axis
Calculations
Lead II
• The normal range of the MFPA is about -30 to +90 however this is affected by
how the heart lies in the chest wall and upon muscle mass.
• If MFPA is 60 degrees then Lead II would be exactly on the MFPA therefore
the signal would be at its maximum. As the hypotenuse is the longest
possible line.
Lead I
• However Lead I= MFPA cos a
○ I= MFPA x 0.5therefore lead 1's signal strength is half the max size.
Understand what is meant by the terms left and right axis deviation,
and how these conditions may occur
• Left axis deviation is where the MFPA< 30 degrees.
• Right axis deviation is where the MFPA>90 degrees.
• Left axis deviation can be caused by malfunctioning valve and hypertrophy of
left ventricle which would shift MFPA to the left.
• Right axis deviation can be caused by right ventricular hypertrophy which
may signal pulmonary disease.
aVF
• The aVF= MFPA cos b
○ MFPA cos 30
○ aVF= MFPA x 0.87
Overall in this example:
• Lead I<aVF< Lead II
• Lead aVL would be 0
• Furthermore as Cos90 = 0 therefore any lead that is perpendicular to the
MFPA will have a signal strength of zero.
• Finally as Cos 90- 270 degrees is negative the ECG will show a downwards
deflection rather than an upwards one.
Location of Chest Electrodes
Location of the Chest Electrodes
V1- 4th intercostal space right sternal edge
V2- 4th intercostal space left sternal edge
V3- Directly halfway between V2 and V4
V4- 5th intercostal space mid- clavicular line
V5- Anterior axillary line directly lateral to V4
V6- Mid- axillary line directly lateral to V4.
qR
rS
Stuart's Cardiovascular System Page 11
TRANSITION ZONE
Microcirculation
31 January 2012
14:04
Learning Objectives
Describe the branching structure of the microvasculature. List the
three types of capillary and order them in terms of their permeability to
water and small lipophobic solutes
Describe the branching structure of the microvasculature. List the three types
of capillary and order them in terms of their permeability to water and small
lipophobic solutes
st order arterioles
11st
Order Arterioles
Describe the factors controlling capillary blood flow and explain the
functional importance of capillary density
Terminal
arterioles
Terminal arterioles
Identify the different mechanisms by which solute is transported
between blood and tissue (depending on size and lipid solubility).
Capillary
Capillary
Explain how the “Starling forces” influence fluid transfer across the
capillary wall
Describe the origin of lymph fluid. Describe the branching structure of
the lymphatic system. Understand how clinical oedema arises
Pericytic-(post-capillary
Post-capillary venule
Pericytic
venule
Venule
Venule
Describe the factors controlling capillary blood flow and explain the
functional importance of capillary density
• The overall aim of the CVS is to have adequate blood flow through the capillaries
so that diffusion can occur.
• Blood flow rate= Volume of blood passing through a vessel per unit time.
• Maximal pressure in system versus pressure as you leave the arterioles and join
the capillaries.
Flow = Pressure gradient/ resistance
Resistance:
Hindrance to blood flow due to friction between moving fluid and stationary vascular
walls.
Factors affecting resistance:
1. Blood viscosity
2. Vessel length
3. Vessel radius- Only one that is easily changeable
R 1
r4
e.g. r halved  R  16 fold
Identify the different mechanisms by which solute is transported between
blood and tissue (depending on size and lipid solubility).
• Capillary walls act as semi-permeable membranes. Electrolytes and small lipophilic
molecules cross the wall much more easy than plasma proteins.
1. Small lipid- soluble molecules such as oxygen, carbon dioxide can diffuse through
the lipid bilayer.
2. Small lipid- insoluble molecules cannot easily cross plasma membranes and thus
must pass through the small water filled gap junctions. There is a layer of
negatively charged macromolecules (glycocalyx) which covers the endothelial
cells and lines the water filled channels. These contribute to the permeability
characteristics of the cell membrane. Small ions may cross this way in addition to
molecules such as glucose, amino acids and drugs.
3. Large lipid-insoluble molecules are particularly affected by the type of capillary
for example they find it very hard to cross continuous capillaries. However some
plasma protein can leak out of the circulation and be present in the interstitial
space at levels 20-70% of the blood plasma. This is important because many
hormones, vitamins and lipids are transported bound to proteins. They can also
cross membranes via endocytotic vesicles.
Explain how the “Starling forces” influence fluid transfer across the
capillary wall
Fluid Movement Across Capillary:
• Bulk Flow- A volume of protein free plasma filters out of the capillary, mixes with
the surrounding interstitial fluid and is reabsorbed.
• Hydrostatic pressure forces liquid out of the capillaries and into the tissue.
• Oncotic pressure transfers liquid back into the blood vessels. This is caused by
the osmotic effect of the plasma proteins within the blood.
Starling's law is that there must be balance between these two forces.
Stuart's Cardiovascular System Page 12
Microvessels
Arterioles:
• The arterioles are THE major resistance vessels. The Mean Arteriole Pressure is about
93mmHG (MAP) whereas the pressure located within the capillary bed is only about
37mmHg.
• Within an organ the flow rate is determined by the MAP and the resistance within the
organ itself.
• Vascular Tone- Arteriolar smooth muscle normally display a state of partial constriction.
• Radii of arterioles are adjusted independently to accomplish two functions:
i. Match blood flow to the metabolic needs of specific tissues (depending on
body's momentary needs)
□ Regulated by local intrinsic controls
□ Independent of nerves or hormones
ii. Help regulate arterial blood pressure
□ Regulated by extrinsic controls.
Match blood flow to the metabolic needs of specific tissues:
• Chemical- An increase in metabolism will result in an increase in oxygen usage and
consumption which will cause vasodilation. This process is known as 'Active
Hyperaemia'.
• Physical- A decrease in blood temperature causes vasoconstriction.
• Physical stretch- An increased arteriole BP causes higher level of stretching within the
smooth muscle surrounding the arterioles. This will cause Myogenic Vasoconstriction
which is a form of Autoregulation. The stretching causes the smooth muscle cells to
open ion channels and cause muscular contraction. This significantly narrows the lumen
of the arteriole so that blood pressure increases. The point of this is so that high BP can
be maintained.
Help regulate arterial blood pressure:
•
•
•
•
•
FLOW RATE= CHANGE IN PRESSURE/ RESISTANCE
Resistance is dependent upon TPR or total peripheral resistance.
Pressure is dependent upon Mean Arteriole Pressure
Flow is Cardiac Output.
Therefore:
MAP= CO x TPR
Relation to nervous system:
• Cardiovascular control centre in the medulla.
• Alpha 2 receptors in blood vessels cause vasodilation.
• Beta receptors in the heart increase Cardiac Output.
Relation to hormonal system:
• Vasopressin and Angiotensin II are vasoconstrictors.
• Adrenaline and noradrenaline are part of the sympathetic activity of the ANS.
Capillaries:
• Capillary exchange- The delivery of metabolic substrate to the cells of the organism.
• Tiny blood vessels only 7µm in diameter.
• Ideally suited to enhance diffusion via Fick's law- minimize diffusion distance and
maximise surface area diffusion time.
• Highly metabolically active organs usually have a more dense capillary bed. However the
Pre-capillary sphincter can limit blood flow if it is not needed or it is more important for
it to go elsewhere.
• Lung extremely dense 3500cm2/g, skeletal muscle less so at 100cm2/g.
• Between endothelial cells there are water filled gap junctions. Lipid soluble things can
diffuse through membrane of endothelial cells. Hydrophilic dissolve in water.
• Highly metabolically active organs usually have a more dense capillary bed. However the
Pre-capillary sphincter can limit blood flow if it is not needed or it is more important for
it to go elsewhere.
• Lung extremely dense 3500cm2/g, skeletal muscle less so at 100cm2/g.
• Between endothelial cells there are water filled gap junctions. Lipid soluble things can
diffuse through membrane of endothelial cells. Hydrophilic dissolve in water.
Types of Capillary:
• Continuous:
○ Least permeable type of capillary and are found in skin, muscle, lungs and the
nervous system.
○ They have tight junctions in between adjacent endothelial cells which only allow the
passage of relatively small molecules.
○ Blood brain barrier is formed by astrocytes- this restricts access to the brain tissue
by certain types of cell.
• Fenestrated
○ Slightly larger gap junctions that allow bigger molecules to get through.
○ Examples are capillaries in glomerulus of the kidneys, intestinal villi and choroid
plexus of the brain- CSF.
○ Fenestrae are typically 50-60nm and are covered by a very thin diaphragm derived
from the Glycocalyx.
• Discontinuous
○ Found in tissues such as bone marrow, liver and spleen where there is a need for
red cells to enter and exit the circulation.
○ Gaps may be over 100nm which is just big enough for the 8000nm red cells to
squeeze through- seemingly contortionists!
• If pressure inside the capillary is greater than in the IF Ultrafiltration occurs.
• If inward driving pressures are greater than outwards pressures across the
capillary than Reabsorption occurs.
• Usually a net loss of to the tissues which is dealt with by the Lymphatic system.
Describe the origin of lymph fluid. Describe the branching structure of the
lymphatic system. Understand how clinical oedema arises
Structure of Lymphatic Capillaries:
• Lymph capillaries are blind ended tubes that are only one endothelial cell thick.
• The cells sit on an incomplete basement membrane and overlap in such a way that a
valve like mechanism is caused thus only water can enter the lacteals.
• The valve like mechanism is kept open by Anchoring Filaments.
The functions of the lymphatic system can be summarized as follows:
1. Tissue drainage system which helps to maintain appropriate body water distribution.
2. Return of plasma proteins which have leaked out into the interstitial space back to the
circulation via ducts entering the venous drainage of the arms.
3. Absorption of digested fat in the form of chylomicrons into the lacteals (lymph
capillaries) of the gut.
4. Defence function at lymph nodes mediated by phagocytic cells and by lymphocytes.
○ DART- is the acronym
Lymph Flow:
• Within the lymphatic system there is no heart to generate pressure and thus the flow of
the lymph. Instead this system is dependent upon skeletal muscular contractions within
the leg and also upon the breathing mechanism.
• The Right and Left Subclavian Veins are the main drainage point for the Right Lymphatic
Duct and Thoracic Duct.
• Approximately 3L of lymph is processed a day.
Oedema:
• Oedema- Excess accumulation of water in body fluid compartments.
• This can be caused by 4 main factors:
a. An increase in capillary blood pressure
b. A decrease in plasma colloid osmotic pressure
c. Blockage of the lymphatic drainage.
d. An increase in capillary permeability.
Stuart's Cardiovascular System Page 13
Mechanical Action of the Heart 2
31 January 2012
14:28
Learning Objectives
Describe the mechanical events of the cardiac cycle
State the origin of the heart sounds
Describe the mechanical events of the cardiac cycle
State the origin of the heart sounds
Diastole- Ventricular relaxation which causes it to fill with blood. 4 sub phases
Systole- Ventricular contraction 2 sub phases
Use a graph to correlate electrocardiographic events and pressure events of
the atria, ventricles, aorta and pulmonary artery
Indicate on the graph the phases of the cardiac cycle and the corresponding
pressure changes, valve openings and closures
Define and state normal values for right and left ventricular end-diastolic
volume, end-systolic volume, stroke volume, end-diastolic pressure and
peak systolic pressure
Provide the mathematical equation for ejection fraction
Define cardiac output and indicate its determinants
Construct simple pressure-volume diagrams from the events during the
cardiac cycle and annotate these graphs appropriately
Use a graph to correlate electrocardiographic events and pressure events of
the atria, ventricles, aorta and pulmonary artery
Indicate on the graph the phases of the cardiac cycle and the corresponding
pressure changes, valve openings and closures
Cardiac Cycle
• The cardiac cycle can be split into 7 stages:
1) Atrial systole
2) Isovolumic contraction
3) Rapid ejection
4) Reduced ejection
5) Isovolumic relaxation
6) Rapid filling of ventricles
7) Reduced filling of ventricles
• A, C and V are waves detectable in the jugular vein.
• PQRST are waves commonly detected on an ECG machine.
• Convention dictates that we start with atrial systole.
Atrial Systole
• Passive filling of ventricles is topped up by atrial contractions.
• Able to feel pressure of atria in jugular vein because its near Vena Cava.
• Contraction of atria causes small amount of blood to go back up Vena Cava- creates a
small A wave.
• P wave is atrial depolarization by the SA node.
• 4th heart sound- abnormal and occurs with congestive HF, pulmonary embolism or
tricuspid incompetence.
Isovolumic contraction
• This is the interval when all the valves are shut. Period of isometric force production to
increase pressure within the ventricles.
• AV valves shut when ventricular pressure exceeds atrial pressure.
• QRS complex marks ventricular depolarization.
• 1st heart sound- due to closure of AV valves and associated vibrations.
Rapid Ejection:
• Aortic and pulmonary valves open and mark this phase
• Small discernible C wave in jugular vein because of RV pushing against tricuspid valve and
sending more blood up vena cava.
Reduced Ejection:
•
•
•
•
This phase marks the end of systole.
Semi-lunar valves start to close.
Blood flow from ventricles decreases and ventricular volume decreases more slowly
As pressures in ventricles fall below that in arteries, blood begins to flow back causing SL
valves to close.
• T wave is due to ventricular repolarisation
Isovolumic relaxation:
•
•
•
•
•
The beginning of diastole.
The semi-lunar valves have just shut and remain closed until the end of this phase.
Atria fills with blood despite the AV valves being shut therefore pressure increases in atria.
Blood pushing tricuspid valve gives second jugular pulse- V wave.
Blood pushes aorta apart slightly- therefore it rebounds slightly which causes a wave- the
Dichrotic notch
• 2nd heart sound (dub) occurs when aortic and pulmonary valves close.
Rapid ventricular filling:
• Once AV valves open blood flows into ventricles.
• 3rd heart sound can occur due to hypertension or mitral incompetence which causes
turbulent ventricular filling.
Define and state normal values for right and left ventricular end-diastolic
volume, end-systolic volume, stroke volume, end-diastolic pressure and
peak systolic pressure
• The patterns of pressure changes in the right heart are essentially identical to
those of the left.
• Quantitatively the pressures in the right heart and pulmonary circulation are much
lower.
• Despite the lower blood pressure both sides of the heart pump the same volume
of blood
Reduced ventricular filling:
• Sometimes known as diastasis whereby the ventricles fill much more slowly.
Heart Sounds
Lub= AV valves shut isovolumic contraction
Dub= A+P valves shut during isovolumetric relaxation
Rapid filling= mitral incompetence or hypertension
Atrial systole= tricuspid incompetence, PE or CHF.
Provide the mathematical equation for ejection fraction
Extra Waves/ Abnormalities
A- atrial systole pushing up IVC
C- rapid ejection pushing back
against tricuspid.
V- isovolumetric relaxation
Dichrotic notch- Blood pushes
apart aorta so it rebounds during
isovolumetric relaxation.
Ejection fraction= SV/EDV
Ours would be around 65% - heart failure would be about 35%
Think- 'A' atrial, 'C' contraction
and 'V' volumetric.
1.
2.
3.
4.
End-diastolic and systolic volume
• Right ventricular and left ventricular must be the same for total blood flow to be
equal.
• 130ml= end diastolic volume
• 60ml= end systolic volume
Stroke Volume
Define cardiac output and indicate its determinants
• End diastolic volume- End systolic volume= Stroke Volume
• Approximately 70ml.
Stuart's Cardiovascular System Page 14
Cardiac Output= Stroke volume x Heart Rate.
Stroke Volume
Define cardiac output and indicate its determinants
• End diastolic volume- End systolic volume= Stroke Volume
• Approximately 70ml.
End-diastolic pressure
• RHS- About 3-8 mmHg
• LHS- About 3- 12 mmHg
Peak systolic pressure
Cardiac Output= Stroke volume x Heart Rate.
Determinants:
• Autonomic nervous system activity.
• Hormones such as adrenaline.
• Pathophysiology of CVS disorders. E.g. valve defects, left ventricular hypertrophy.
• Preload
• Afterload
• Contractility
• RHS- 15-30 mmHg
• LHS- 100-140 mmHg
Construct simple pressure-volume diagrams from the events during the cardiac
cycle and annotate these graphs appropriately
Define cardiac output and indicate its determinants
Cardiac contractility
Definition: Contractile capability (or strength of the heart)
• Simple measure of cardiac contractility is ejection fraction
• Contractility is increased by sympathetic stimulation
• Family of different Frank-Starling relations as cardiac contractility changes
Changes that occur during exercise:
• During exercise contractility is increased due to increased sympathetic activity.
• During exercise end diastolic volume is increased due to changes in the peripheral
circulation (venoconstriction and muscle pump)
•
•
•
•
Point 1 on this graph represents End Diastolic Volume of the LV.
Point 2 is the aortic pressure that is encountered/isovolumic contraction
Point 3 is the end-systolic volume.
Point 4 is probably during isovolumic relaxation
• Blood filling the ventricle during diastole determines the preload and the amount of stretch.
• The blood pressures in the great vessels (aorta and pulmonary artery) represent the afterload.
Remember from previous lecture that as afterload increases, the amount of shortening that
occurs decreases
Stuart's Cardiovascular System Page 15
ECG- Disturbances in cardiac rhythm
10 February 2012
09:11
Learning Objectives
Recognize common abnormalities of cardiac rhythm on the ECG
Recognize common abnormalities of cardiac rhythm on the ECG
• Brachycardia○ Common symptoms include blackout, fatigue and loss of consciousness
○ Heart rate of less than 60 BPM
• Tachycardia
○ Results in shortness of breath.
○ Typically has to be greater than 100 BPM
• Cardiac conduction abnormalities○ AV + SA Node in sync rather than delayed slightly.
• Supraventricular arrhythmias:
○ The chance of atrial fibrillation is 15% when greater than 75.
○ Atrial flutter, AVNRT present with breathlessness
• Ventricular arrhythmias
○ Ventricular tachycardia, fibrillation
Know the normal duration and amplitude of the components of the ECG
waveform
Recognize normal sinus rhythm on the ECG
Describe a systematic approach to ECG interpretation
Recognize a common pattern of acute myocardial infarction on the ECG
Know the normal duration and amplitude of the components of the ECG
waveform
P wave
Duration < 0.11s,
Amplitude < 2.5mm in lead II
PR Interval
0.12-0.20s
Describe a systematic approach to ECG interpretation
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
QRS complex Duration < 0.12s
Amplitude: R wave in V6 < 25mm, or R wave in V6 + S wave V1
< 35mm
Axis: -30 to + 90 degrees
Q wave
Duration < 0.04s
Amplitude: < 25% of total QRS complex amplitude
QT interval
0.38-0.42s (corrected for heart rate)
ST segment
Should be isoelectric
T wave
May be inverted in III, aVR, V1 and V2 without being abnormal
Is it the correct recording
Identify the leads
Check the calibration and speed of the paper
Identify the rhythm
Look at the QRS axis
Look at the P wave
Look at the PR interval
Look at the QRS complex
Determine the position of the ST segment
Calculate the QT interval
Look at the T wave
Recognize common abnormalities of cardiac rhythm on the ECG
•
•
•
•
•
Sinus tachycardia
Heart rate is >100BPM
Rhythm is regular
P waves have normal morphology
Atrial rate and ventricular rate is 100-200 BPM
Regular ventricular rhythm.
Atrial fibrillation
• A- 350-650 BPM
• V: Slow to rapid (100-180)
• May develop clots in their heart due to irregular
rhythm and blood flow.
• P wave- Fibrillatory (fine to course)
• PR interval varies.
• Coronary artery disease or hypertension
Atrial flutter:
A: 220-430BPM
V: <300 BPM
Rhythm regular or variable
Regular ventricular rhythm.
P wave- Undulating saw-toothed baseline
F (flutter) waves
• QRS< 0.12 s
•
•
•
•
•
Recognize a common pattern of acute myocardial infarction on the
ECG
•
•
•
•
•
Deep and wide Q wave in old MI.
Long QT interval predisposes people to sudden death
ST elevation in infarction
ST drop/ trough in angina.
Hypertrophic myopathy? T wave inversion
Bundle Branch Blocks
• SA Node-> AV Node-> Bundle of His-> Bundle Branches-> Purkinje Fibres.
• Depolarization of bundle branch and purkinje are seen as the QRS complex.
Therefore a bundle branch block manifests as an alteration in the QRS complex
on an ECG readout.
Preexcitation syndrome:
• Pathway causing early conduction between
both nodes. Wolf Parkinson White Syndrome.
• P wave is identical before each QRS.
• QRS usually >.10.
• Predisposed to arrhythmias, tachycardia etc.
• Delta wave distorts QRS.
Heart block: (AV Nodal Block)
1st degree- Prolonged PR interval
Two ECG changes:
1. QRS Complex widens to >0.12 seconds.
○ When the conduction pathway is blocked it will take longer for the electrical
signal to pass throughout the ventricles
2. QRS Morphology changes (varies depending on ECG lead, and if it is R vs. L BBB.
○ In RBBB the wide QRS complex assumes a unique, virtually diagnostic in
those leads overlying the right ventricle (V1 and V2). The shape is known as
Rabbit Ears.
○ May be causes by a Atrial Septal Defect.
V1
Stuart's Cardiovascular System Page 16
2nd degree- Mobitz type I and II
Type 1 (Wenckebach)- Gradually increasing PR interval until it drops
V1
○ In LBBB the wide QRS complex assumes a characteristic shape in these leads
opposite the left ventricle (V1 and V2). The shape is a broad deep S wave.
Type II- Normal PR interval then complete drop off QRS complex
○ Causes:
 Hypertension, aortic stenosis, dilated cardiomyopathy.
 Worse prognosis than RBBB- losing a lot of functionality of the
myocardium 30% of efficiency is lost. Cardiac re synchronisation
therapy is necessary.
3rd degree- Complete heart block
○ No correlation between PR interval and QRS complex, slow heart rate.
•
•
•
•
•
•
Stuart's Cardiovascular System Page 17
Ventricular Tachycardia:
Ventricular Fibrillation- They need CPR urgently, medical emergency.
Heart rate 300-600
No regular rhythm
P wave is absent
No PR interval
QRS- fibrillatory baseline
Blood Vessels and Blood Flow
10 February 2012
10:04
Learning Objectives
Understand the role and design of the normal circulation
Understand the role and design of the normal circulation
Be able to describe physical factors influencing flow
Know ‘Ohms law for the circulation’ and the principles of the Poiseuille’s
equation
Understand how the compliance of the aorta and elastic arteries affect the
pulse pressure
Be able to describe physical factors acting on blood vessels and know the
Laplace equation
• To transport blood around the body (gases, nutrients, metabolites, ions,
hormones, heat)
• Flow is achieved by the action of a muscular pump (heart) propelling blood
through a network of tubes (blood vessels).
• The circulation consists of two such pumps (left and right ventricle) which are
physically coupled and pump through the systemic and pulmonary
circulations respectively.
• Diffusion is crucial for movement of materials through tissues.
• Diffusion is only effective over short distances so a capillary needs to be ~10
µm from every cell. This necessitates a highly branched structure.
Large veins
Large (elastic) arteries
Know the basic mechanisms by which flow of blood and transmural
pressure influence blood vessel structure and function
Understand how standing (gravity) affects the circulation
Medium sized veins
Small (muscular) arteries
Relative areas and volumes in the circulation
Relative cross-sectional area
Blood Volume (Total = 5L)
Venules
Arterioles
Aorta
Arterioles
Capillaries
Capillaries
Pulmonary vessels
‘Exchange’ function
‘Reservoir’ function
• 60-70% of total blood volume is actually in veins
Know ‘Ohms law for the circulation’ and the principles of the Poiseuille’s
equation
Ohm's law:
• MBP= CO x PVR
• Mean blood volume= Cardiac output x Peripheral resistance.
• Cardiac output= Stroke volume x Heart rate
Poiseuille's Equation:
• Relationship between pressure and laminar flow in long straight tubes.
• The resistance to flow in a long straight tube depends on the viscosity of the fluid,
the length of the tube and the radius of the tube.
• Large elastic arteries act as conduits and dampening vessels, while muscular
arteries and arterioles are important in regulating blood pressure - particularly
the arterioles.
Be able to describe physical factors influencing flow
Blood pressure
• Blood pressure is the driving force for the flow of blood around the human body and this
is created by the left ventricle.
• Mean Blood Pressure= Cardiac Output x Resistance
• This is an approximation since flow in the circulation is not steady because of the
intermittent pumping of the heart and blood vessels aren't rigid.
• Pulmonary blood pressure is much lower because it has much less resistance in the
vessels.
Pressure throughout the circulation
MBP
Blood supply to organs
large arteries
• Where mu= fluid viscosity, L= vessel length and r = vessel radius.
• This equation emphasizes the importance of arterial diameter as a determinant of
resistance.
• Flow is proportional to d4. Halving of the diameter will cause a 16 fold decrease in
flow.
small arteries
• Resistance = 8µL/ πr4
left heart
Heart
Vena Cava
Pulmonary circ
Venules/veins
right heart
Venules and veins
arterioles
Capillaries
veins
Arterioles
capillaries
Aorta
Pressure falls across the circulation due to viscous (frictional)
pressure losses. Small arteries and arterioles present most
resistance to flow.
• It is important to recognise that it is the difference in pressures between the two systems
that drives flow and not the absolute pressure itself.
Resistance:
• In the normal circulation fluid flows in laminae (layers).
• In theory fluid particles in contact with the surface of the tube are stationary whilst those
at the centre are flowing fastest.
Viscosity, flow and shear
• The dynamic viscosity is a measure of the resistance of a fluid to deform under shear
stress (thickness of fluid).
• The shear rate is the spatial velocity gradient at any point within the graph.
• Shear stress= Shear rate x dynamic viscosity of the fluid.
• Shear stress near the wall is believed to be an important influence on endothelial function
in health and disease.
Understand how the compliance of the aorta and elastic arteries affect the
pulse pressure
Stuart's Cardiovascular System Page 18
Understand how the compliance of the aorta and elastic arteries affect the
pulse pressure
• Kidneys 20% at rest and 4% during exercise.
• Massive relative drop in GI organs. I.e. the percentage drops-however because CO is
much higher the actual level of blood reaching them is still similar.
Be able to describe physical factors acting on blood vessels and know the
Laplace equation
Know the basic mechanisms by which flow of blood and transmural
pressure influence blood vessel structure and function
•
•
•
•
Pulse pressure= Systolic blood pressure - diastolic blood pressure
During ejection blood enters the aortal and other elastic arteries faster than it leaves them.
~40% of the stroke volume is stored by the elastic arteries.
When the aortic valve closes ejection ceases but due to recoil of the elastic arteries pressure
falls slowly and there is diastolic flow in the downstream circulation.
• This damping effect is sometimes termed the ‘Windkessel’
• If arterial compliance decreases (arteries become stiffer), e.g. with age, the damping effect
of the Windkessel is reduced and the pulse pressure increases.
Compliance properties-
• Transmural- Occurring across the entire wall of a blood vessel.
• Laplace's equation explains the relationship between diameter, tension and
pressure
• See Mechanical Action of Heart
• Tension = Pressure x Resistance
• The relationship between the transmural pressure and the vessel volume is called
the compliance and depends on vessel elasticity.
• Circumferential hoop stress- (Tension/ wall thickness (h)- if high over a long period
of time can cause a balloon like distension known as an aneurysm.
Volume
Vein
Understand how standing (gravity) affects the circulation
• The 120cm H20 column of blood has a pressure of 80mmHg in veins in the feet.
• Gravity increases pressure in the lower limbs.
• Due to the compliancy of veins they distend and blood pools here reducing venous
return, preload and thus cardiac output and blood pressure.
Standing causes:
• Activation of baroreceptors in carotid artery and activation of sympathetic nervous
system.
• Release of NA which causes vasoconstriction of veins, more important is making
them stiffer, not really a big change in resistance, but a big change in compliance.
• In arteries diameter is reduced and Blood Pressure increases.
• Myogenic venoconstriction- response to elevated venous pressure.
• Contraction of skeletal muscle in leg causes blood to be pumped up from deep
veins.
• However cerebral blood flow does fall on standing occasionally- head rush?
• Respiratory system and change in interthoracic pressure can cause contraction in
veins. Negative pressure on chest expansion sucks blood into the central veins.
• Valvular incompetence causes dilated superficial veins in the leg (varicose veins)
• Prolong elevation of VP causes oedema in feet.
Stuart's Cardiovascular System Page 19
Artery
Pressure
•
•
•
•
Relationship between pressure and volume is non-linear.
Collagen limits distension, distension is elastin's job.
Pressure 8mmHg 10 cm below heart.
Veins are highly compliant at low pressures- this means that relatively small changes in
venous pressure distend veins and increase the volume of blood stored in them.
Endothelium
10 February 2012
14:01
Appreciate the function of the endothelium as a generator of
hormones that regulate vascular and cardiac muscle form and
function
Appreciate the function of the endothelium as a generator of hormones
that regulate vascular and cardiac muscle form and function
Describe ways in which the endothelium can be stimulated and how
this results in release of the named hormones: NO, prostacyclin,
endothelin-1.
Describe in general terms the renin-angiotensin system and know
how its major components regulate vascular function
Describe how the following work:
low dose aspirin
nitrovasodilators
calcium channel blockers
Appreciate why these drugs carry side effect risks along with their
therapeutic benefits
Endothelial cells secrete:
Appreciate the function of the endothelium as a generator of hormones that
regulate vascular and cardiac muscle form and function
Nitric oxide:
• Causes smooth muscle relaxation and inhibition of growth.
• Increases blood flow to myocytes and has an effect on contractility
• Also stops the aggregation of platelets.
• Potent vasodilator
Prostacyclin/PGI2
• Has the same effects as nitric oxide but doesn't affect contractility.
• Vasodilator
• Vasodilators decrease intracellular calcium levels.
•
•
•
•
Nitric oxide
Prostacyclin (Prostaglandin I 2) and thromboxanes
Endothelin-1
Angiotensin II- converted by enzyme that is present here from a precursor
Targets include:
• Smooth muscle
• Myocytes
• Platelets
Describe ways in which the endothelium can be stimulated and how this
results in release of the named hormones: NO, prostacyclin, endothelin-1.
Nitric oxide
Thromboxane• Contraction of smooth muscle
• Reduces myocyte blood flow
• Stimulates aggregation of platelets
• Vasoconstrictor
• Sheer force stimulates nitric oxide release.
Endothelin-1
• Causes contraction of smooth muscle and a weak stimulation of their growth.
• Reduces blood flow to myocytes and increases contractility.
• Potent vasoconstrictor/ increase blood pressure.
Angiotensin II• Contraction and stimulation of growth of smooth muscle
• Reduces blood flow to myocytes and is also involved in cardiac remodelling and
fibrosis
• Potent vasoconstrictor.
ACh
L-arginine
analogues
PLC/IP3
Ca2+
eNOS
Endothelium
L-arginine
NO
Short t1/2
sGC
• Vasoconstrictors increase intracellular calcium levels.
Describe in general terms the renin-angiotension system and know how its
major components regulate vascular function
cGMP
PKG
Ca2+
Short t1/2
Smooth Muscle
Renin-Angiotensin System
From the Liver
From the Kidney
On endothelial cells
ACE
Inhibitors
ACE
Inhibitors
• Stimulation of ACh causes this pathway to be initiated.
• Remember this parasympathetic innervation will cause vasodilation.
Pathway
• Endothelial nitric oxide synthase cleaves NO from L-arginine which diffuses across to
smooth muscle cell.
• Soluble Guanylate Cyclase releases cGMP which regulates protein kinases which
lowers cellular calcium concentration.
• This then decreases the ability of the muscle to contract.
• NO has a very short half life.
Effects
• Flow induced vasodilation- fundamental to its action, response to increased sheer
stress.
• Vasodilation in the skin due to temperature change to help manage
thermoregulation.
• Penile erection mediated by increased flow dilation of the corpus cavernosum.
Receptor Antagonists
Stuart's Cardiovascular System Page 20
Prostacyclin/ Thromboxane
• Vasodilation in the skin due to temperature change to help manage
thermoregulation.
• Penile erection mediated by increased flow dilation of the corpus cavernosum.
Receptor Antagonists
1. Renin causes angiotensinogen to change to angiotensin I.
2. ACE is present in endothelial cells and converts angiotensin I to angiotensin II which is
more biologically active. (AT-1 receptors cause vasoconstriction.)
3. ACE inactivates bradykinin which normally stimulates NOS.
Prostacyclin/ Thromboxane
• An enzyme called Cyclo-Oxygenase (COX) mediates the production of prostacyclin
and thromboxane.
• COX-1 is present in a healthy C.V.S whereas COX-2 causes inflammation and pain.
• ACE inhibitors block vasoconstriction which is augmented by increasing NO release.
• Angiotensin II has a number of functions which include inflammation, tissue
remodeling, endothelial dysfunction and oxidative stress.
• Both originate from Arachidonic acid.
• Prostaglandin- IP receptor increases cAMP causes vasodilator, antiatherogenic, anti
platelet.
• Thromboxane- vasoconstrictor- TP receptor, Inositol Triphosphate- Opposite effects.
Endothelin
Describe how the following work:
low dose aspirin
• 21 amino acid peptide with 2 sulphide bonds.
• Made in endothelial cells, endothelial converting enzyme ECE.
• Endothelin can stimulate ETB receptors to cause endothelial cells to limit effect of
contraction by secreting Nitric Oxide but is generally…..
• An extremely potent vasoconstrictor
• Upsets balance between prostacyclin and thromboxane resulting in platelets being
unable to produce thromboxane.
• Endothelial cells are able to synthesise prostacyclin
• Platelets cannot replenish COX enzyme once aspirin is given
• Low dose aspirin lowers prostacyclin and thromboxane levels.
Appreciate why these drugs carry side effect risks along with their
therapeutic benefits
• Our body often uses the same chemical to regulate more than one process
nitrovasodilators
• NO donors - (nitroglycerine, nitroprusside)
• eNOS activators- (endothelium dependent vasodilators)
• Phosphodiesterase inhibitors- Viagra, Zaprinast
• Release NO from their chemical structure
• Viagra- Inhibits enzyme which would otherwise break down cyclic GMP
calcium channel blockers
Lipo-oxygenase
leukotrienes
• Dihydropyridines- Nifedipine
• Phenylalkylamine- Verapamil
Causes Asthma in
3-5% of patients
• Blocking one of COX1 or 2 can cause build up of arachidonic acid-> lipo-oxygenase->
leukotrienes causes asthma in 3-5% of people.
• Dihydropyridine calcium channel blockers are often used to reduce systemic vascular
resistance and arterial pressure, but is not used to treat angina because the
vasodilation and hypotension can lead to reflex tachycardia.
• Bosentan- Blocks endothelin converting enzyme
• Able to regulate contraction, secretion, neurotransmission, gene expression.
Blocking calcium entry into the cell:
• Vasodilatation reduces afterload and thus CO increases.
• Negative ionotropic (decrease work done by the heart) effects occur, oxygen
demand is also reduced.
• They prevent coronary artery vasospasm, which makes them very useful in the
treatment of variant angina.
• Some drugs can be specific for membrane potential of the cells and only block these
calcium channels.
Stuart's Cardiovascular System Page 21
Qu. 4: Vasodilator that stimulates B1 receptors on endothelial cells to
release vasodilator mediators.
Best Option: bradykinin
Sympathetic + Renin-Angiotensin Pathway.
10 February 2012
15:02
Learning Objectives
Describe the principles of the organisation of the sympathetic nervous
system
Describe the synthesis, release and removal of the neurotransmitter,
noradrenaline
Describe the principles of the organisation of the sympathetic nervous
system
• The sympathetic nervous system has various effects on the cardiovascular system such
as causing vasoconstriction and increasing the contractility of the heart.
• There are two sympathetic trunks which lie either side of vertebral column and give off
sympathetic nerves that innervate certain tissues.
• The sympathetic nervous system innervates the thoracolumbar region from T1-L2.
Outline the types of adrenoreceptor in the sympathetic nervous system
Evaluate the cardiovascular effects of infusion of some common
adrenergic agonists
Describe the principles of the organisation of the renin-angiotensinaldosterone system
Describe the biosynthetic pathway for angiotensin II synthesis
Evaluate the individual roles the SNS and RAS play in modulating the
behaviour of the CVS
Recognize some of the pharmacological concepts involved in how
important sympathetic neurotransmitters interact with receptors to
evoke downstream effects
Describe the synthesis, release and removal of the neurotransmitter,
noradrenaline
Outline the types of adrenoreceptor in the sympathetic nervous system
From Autonomic Nervous System
1. Excitatory effects on smooth muscle
○ Alpha-adrenoreceptor-mediated
2. Relaxant effects on smooth muscle, stimulatory effects on cardiac muscle.
○ Beta-adrenoreceptor
Noradrenaline
Beta Receptors
• B1- Cardiac muscle, smooth muscle of gastrointestinal tract
• B2- Bronchial, vascular and uterine smooth muscle
• B3- Found on fat cells and possibly smooth muscle of gastrointestinal tract.
Alpha receptors
• a1- Located post synaptically on effector cells.
○ Important in mediating constriction of resistance vessels. Small arteries and
arterioles in response to sympathomimetic amines
• a2- Located on presynaptic nerve terminal membrane.
○ Negative feedback loop- NA feeds back here and regulates its own release.
○ Some are actually post-synaptic on vascular smooth muscle, but not in very
many vascular beds.
Coupling of Alpha1-adrenoreceptors
Synthesis:
• Tyrosine enters the pre-synaptic neurone and is converted by Tyrosine Hydroxylase to
form DOPA (dihydroxyphenylalanine). This reaction is the rate limiting step.
• DOPA is converted by the enzyme DOPA carboxylase to dopamine.
• Dopamine is then packaged into a vesicle within the enzyme Dopamine β hydroxylase
which converts it to Noradrenaline.
Release:
• The granular vesicle fuses with the varicosity membrane and exocytic channels open.
• The vesicle contents are expelled by exocytosis and biosynthesis and reuptake
mechanisms replenish the granular contents.
Coupling to Beta and Alpha 2- adrenoreceptors
• Unlike with ACh there is no further metabolism of the neurotransmitter after it has
been bound to its receptor. Instead a set of uptake proteins either take it back to the
pre-synaptic neurone (Uptake Protein 1) or to the post-synaptic neurone (Uptake
Protein 2).
• Degredation of the noradrenaline is different depending upon its location:
○ In the PreSN an enzyme called Mono-amine oxidase A breaks down the
noradrenaline back down to its metabolites inside the mitochondria.
 PreMOdona- Presynaptic= Mono-amine oxidase
○ In the PostSN an enzyme called COMT (Catechol-O-Methyl Transferase) degrades
the noradrenaline.
 Way of remembering- "You'll catch a cold if you are broken down"
Evaluate the cardiovascular effects of infusion of some common adrenergic
agonists
• Cardiovascular effects of catecholamines in man: 1-microgram/min infused I.V.
Stuart's Cardiovascular System Page 22
Evaluate the cardiovascular effects of infusion of some common adrenergic
agonists
• Cardiovascular effects of catecholamines in man: 1-microgram/min infused I.V.
Catecholamine Noradrenaline
See T9 Signalling Two for reminder
• Beta receptor are Gs receptors are therefore calcium release is mediated by
adenylase cyclase- Heart causes increased contraction and rate.
• A2- Inhibiting cAMP formation so lets calcium be more active in most cells. cAMP
and calcium are antagonists.
Adrenaline
Isoprenaline
Systolic BP



Diastolic BP



Mean BP


 or 
Heart rate



Effects of catecholamines on activation of
adrenoceptors
Natural
Describe the principles of the organisation of the renin-angiotensinaldosterone system
Noradrenaline
1
2
1
Adrenaline
1
2
1
Dopamine
weak effects at 1 and 1 , but has own receptors
Synthetic
Isoprenaline
Phenylephrine
1
2
2
1
Evaluate the individual roles the SNS and RAS play in modulating the
behaviour of the CVS
Renin-Angiotensin System
• Effects of Angiotensin II
○ Peripheral Resistance
 Direct vasoconstriction
 Enhanced action of peripheral NE
□ Increased NE release
□ Decrease NE uptake
 Increased sympathetic discharge (CNS)
 Release of catecholamines from adrenal
• Overall rapid pressor response
○ Renal function
 Direct effects to increase Na+ in proximal tubule
 Synthesis and release of aldosterone from adrenal cortex
 Altered renal hemodynamics
□ Renal vasoconstriction
□ Enhanced NE effects in kidney
• Slow pressor response
○ Cardiovascular system
 Haemodynamic Effects
□ Increased preload and afterload
 Non-Haemodynamic Effects
□ Increased expression of proto-oncogenes
□ Increased production of growth factors
□ Increased synthesis of extracellular matrix proteins
• Overall causes vascular and cardiac hypertrophy and remodeling.
• Low tubular Na or low BP is detected by Macula Densa cells and causes
Juxtaglomerular cells to release renin which in turn eventually causes the release of
angiotensin II.
Describe the biosynthetic pathway for angiotensin II synthesis
Recognize some of the pharmacological concepts involved in how
important sympathetic neurotransmitters interact with receptors to evoke
downstream effects
Angiotensin II Type I (AT1) Receptors
• G-protein coupled; Gi and Gq
• Also couples to Phospholipase A2
• Located in blood vessels, brain, adrenal, kidney, and heart.
• Activation of AT1 receptors works to increase BP.
Stuart's Cardiovascular System Page 23
Aldosterone
•
•
•
•
•
From adrenal cortex
Aldosterone maintains the body content of sodium, potassium and water.
It increases sodium retention and thus water retention.
It increases potassium and hydrogen ion excretion.
Primary aldosteronism- caused by adenoma and you can detect this by
extremely low potassium.
Chymase- Generates angiotensin II but is not inhibited by ACE inhibitors. Bad effects of
angiotensin II were still present.
Pharmacology- Ace inhibitors interact with the kinin system- bradykinin, pain and
vascular control. Stops the breakdown of bradykinin. Less ATII but more bradykinin
which is a vasodilator.
Angiotensin II Type I Receptor Antagonists
• Actions:
○ No effects on Bradykinin system
○ Selectively blocks effects of Ang II
 Pressor effects
 Stimulation of NE system
 Secretion of aldosterone
 Effects on renal vasculature
 Growth-promoting effects on cardiac and vasculature tissue.
STRESS
SYMPATHOADRENAL- RENIN-ANGIOTENSIN
SYSTEM
SYSTEM
BLOOD
PRESSURE
PLATELET
ACTIVATION
HEART
RATE
COAGULATION
SODIUM/
FIBRINOLYSIS
WATER
RETENTION
Stuart's Cardiovascular System Page 24
• Aldosterone receptors are present in the kidneys, the brain, blood vessels and
the heart.
Regulation of CVS
14 February 2012
14:04
Learning Objectives
Describe the local mechanisms that regulate blood flow
Key Equations
• Stroke volume = end-diastolic volume - end systolic volume
• SV = EDV - ESV
Describe how blood vessel diameter and heart rate are controlled by the
autonomic nervous system
• Cardiac output = heart rate x stroke volume
Describe how the autonomic nervous system changes the force of
contraction of the heart
• Mean systemic arterial pressure = cardiac output x total peripheral
resistance
• CO = HR x SV
State the location of the baroreceptors
• Mean BP = CO x TPR
Define cardiac output, stroke volume and mean systemic arterial pressure
and state their determinants
Veins in RHS of the body can act as a blood storage mechanism- this is known
as capacitance.
Indicate, using simple flow diagrams, how baroreceptors control blood
pressure
Breathing in causes blood to return to heart more easily due to negative
pressure.
Describe the changes in impulse activity in the carotid sinus nerve,
parasympathetic and sympathetic nerves to the heart and sympathetic
vasoconstrictor nerves that take place following an increase or decrease in
mean blood pressure
Construct an integrated picture of the various systems that control blood
pressure and be able to apply this to specific clinical examples involving
blood loss or fluid overload
Describe the local mechanisms that regulate blood flow
Veins: Constriction determines compliance and venous return.
Arterioles: Constriction determines
• Blood flow to organs they serve
• Mean arterial blood pressure
• The pattern of distribution of blood to organs.
Flow is changed primarily by changing vessel radius.
Describe how blood vessel diameter and heart rate are controlled by the
autonomic nervous system
• Sympathetic nerve fibres innervate all vessels except capillaries and pre-capillary
sphincters and some meta-arterioles
• Large veins and the heart are also sympathetically innervated.
• Distribution of sympathetic nerve fibers elsewhere is variable. More innervate the
vessels supplying the kidneys, gut, spleen and skin and fewer innervate skeletal muscle
and the brain.
• NA binds to alpha-1 receptors to cause smooth muscle contraction and
vasoconstriction.
Vasomotor centre (VMC) in the brain
• VMC is located bilaterally in the reticular substance of the medulla and the lower third
of the pons. The VMC is composed of a vasoconstrictor area (pressor), a vasodilator
(depressor)
• The VMC transmits impulses distal through the spinal cord to almost all blood vessels.
• Many higher centres of the brain such as the hypothalamus can exert powerful excitatory
or inhibitory effect on the VMC.
• Lateral portion of the VMC controls heart activity.
F= Change in pressure/ Radius
Local mechanisms regulating blood flow
• Autoregulation - The intrinsic capacity to compensate for changes in perfusion pressure
by changing vascular resistance.
• Myogenic theory- Smooth muscle fibres respond to pressure in the vessel walls. Stretch
activated ion channel (particularly calcium) may open and cause constriction.
• Metabolic theory- As blood flow decreases "metabolites" accumulate and vessels
dilate, when flow increases "metabolites" are washed away. e.g. CO2, H+, adenosine,
K+.
• Injury (serotonin release from platelets causes constriction)
• Substances released from the endothelium such as Nitric Oxide which is a powerful
vasodilator.
• Prostacyclin and thromboxane A2 relative amounts are important for clotting.
• Endothelins (powerful vasoconstrictor).
Circulating hormones
• Kinins- Tend to relax smooth muscle
• ANP- Atrial natriuretic peptide. Secreted from the cardiac atria which is a vasodilator.
Released is caused by overstretching.
• VASOCONSTRICTORS:
○ ADH- Vasopressin secreted from posterior pituitary
○ Noradrenaline released from the adrenal medulla
○ Angiotensin II formed by increased renin secretion from kidney.
Cardiac output = stroke volume x heart rate
Cardiac output
Stroke volume
Describe how the autonomic nervous system changes the force of
contraction of the heart
Think this was a past exam question
• Both autonomic fibers terminate on the sino-atrial node.
• Sympathetic nerve fibers- more NA released increases gradient of pre-potential so that
action potential is achieved earlier.
• Binding of NA to beta 1 adrenergic increases the amount of cyclic AMP, Protein kinase A.
Phosphorylation of uptake mechanism and calcium channels. More calcium floods into
the cell and leaves the sarcoplasmic reticulum therefore more powerful contraction.
Stuart's Cardiovascular System Page 25
Intrathoracic
pressure
Respiratory movements
Venous return
Heart rate
Plasma
adrenaline
End-diastolic
ventricular
volume
Atrial
pressure
Fight or flight
response
Activity of
sympathetic
nerves to heart
Activity of
parasympathetic
nerves to heart
Describe the changes in impulse activity in the carotid sinus nerve,
parasympathetic and sympathetic nerves to the heart and sympathetic
vasoconstrictor nerves that take place following an increase or decrease in
mean blood pressure
parasympathetic and sympathetic nerves to the heart and sympathetic
vasoconstrictor nerves that take place following an increase or decrease in
mean blood pressure
Phosphorylation of uptake mechanism and calcium channels. More calcium floods into
the cell and leaves the sarcoplasmic reticulum therefore more powerful contraction.
State the location of the baroreceptors
•
•
•
•
Baroreceptors are located in the carotid sinus and the aortic /arch.
Aortic arch feedback via the vagus nerve.
Carotid sinus via the glossopharyngeal nerve.
Retard it says carotid not coronary!!! Carotid is artery is much more superior than
aortic arch therefore it has to be innervated by the glossopharyngeal nerve.
• Respond to pressures between 60 and 180mmHG at its most sensitive at
90-100mmHG.
• Parasympathetic nervous system directly responds to the activity of the
baroreceptors.
• Decreased sympathetic activity via an interneurone.
Indicate, using simple flow diagrams, how baroreceptors control blood
pressure
haemorrhage
Blood volume
Venous pressure
Venous return to heart
Atrial pressure
Venous constriction
Ventricular end
diastolic volume
Sympathetic discharge
to veins
Stroke volume
Arterial blood pressure
Baroreceptor feedback & reciprocal innervation
Cardiac output
reflexes
Construct an integrated picture of the various systems that control
blood pressure and be able to apply this to specific clinical examples
involving blood loss or fluid overload
Mean systemic arterial pressure = cardiac output x total peripheral resistance
Arterial pressure
haemorrhage
Cardiac output
Heart rate
CO = HR x SV
Stroke volume
Arterial pressure
Ventricular end
diastolic volume
Venous return
Venous pressure
Firing of
baroreceptors
Parasymp
discharge
to heart
Reflexes
Stuart's Cardiovascular System Page 26
Peripheral
resistance
Cardiac
contractility
Venous tone
Symp discharge
to heart
Symp discharge
to veins
Arteriolar
constriction
Symp discharge
to arterioles
increase
decrease
Venous pressure
Cardiovascular Stress
14 February 2012
16:02
Movement from a supine to standing position
Learning Objectives
Describe the cardiovascular problems associated with:
movement from a supine to standing position
haemorrhage
exercise
Explain how the components of the cardiovascular system respond to these
various challenges
Haemorrhage
• Reduction in actual circulating blood volumes.
• Decreased baroreceptor firing- attempts to increase heart contractility and heart rate,
in addition to organ specific vasoconstriction.
• Vertical position:
a. Usual pressure resulting from cardiac contraction
b. Effect of gravity on column of blood
e.g. in a foot capillary, the pressure is:
a. 25mmHG
b. 80mmHG
Giving a total of 105 mmHG
• Change of posture massively increases the hydrostatic blood pressure in the veins
in the legs, causing a large amount of venous distension.
• Large amount of CO can be residing in the legs and not in the important places i.e.
capillaries of organs.
• Hydrostatic pressure drives blood out of microcirculation and into tissue cells
Starling's Law
• Ventricular filling during diastole determines level of stretch and stroke volume.
• As a result of haemorrhage there is decreased hydrostatic pressure across the
capillaries.
○ Hydrostatic pressure is higher at the arteriolar end of the capillary (the start)
○ Colloid osmotic pressure, created by plasma proteins which draws fluid back in.
○ Excess ultrafiltration is accounted for by lymphatic system.
• Change of posture causes a transient hypotension this is caused by decreased
ventricular filling due to pooling of blood in the veins.
Compensatory mechanisms
Arterial baroreceptors:
• Carotid sinus
• Aortic arch
• Movement of fluid from tissues back into blood is known as Autotransfusion. Clearly
this does not replace erythrocytes but instead substitutes the cells with liquid to
maintain blood pressure.
• Mass reduction in urine output as a result of stimulation of vasopressin secretion.
• Angiotensin II release also helps because it is a powerful vasoconstrictor.
• Aldosterone promotes sodium and water retention.
• Baroreceptors send an afferent nerve to the CNS. Less baroreceptor firing causes
less parasympathetic nerve action and thus greater sympathetic nerve action.
Effect of decreased blood volumes
• <10% 500ml results in no change in BP
• 20-30% 1-1.5l decrease in BP will survive without any major intervention
• 30-40% 1.5l-2l - Shock- acute circulatory failure tissues are insufficiently perfused.
What to do?
• Don’t cover in a blanket, the skin arterioles will dilate and you will drastically lower
their blood pressure.
• Increase blood pressure via fluids then once blood has been matched do a
transfusion.
Exercise
• At rest only 10% of skeletal muscle arterioles are dilated.
• Increase blood flow will cause a massive drop in TPR.
• Skeletal muscle starts to be utilized, tissue starts using up more oxygen and
generating more waste products. Active Hyperemia caused by oxygen usage.
Control mechanisms
• 'Preprogrammed pattern'- Medullary Cardiovascular Centre
• Muscle chemoreceptors are also sending afferent signal to the MCC.
• The MCC then has effects on sympathetic and parasympathetic neurones and
therefore can affect the function of the whole cardiovascular system.
TPR:
• Profound sympathetically driven vasoconstriction of vascular beds is not necessary
for exercise- i.e. GIT and kidney.
• There is reduced sympathetic input into the skin, which stops vasoconstriction
needed to dilate to dissipate the heat.
• Net result is a drop in TPR but its not as great as it could be.
Cardiac Output:
• Increased SV and HR via increased sympathetic activity and decreased
parasympathetic activity.
• Starlings law- Increased venous return due to skeletal muscle pumps means that
Stuart's Cardiovascular System Page 27
Increased sympathetic discharge results in:
a. Increased heart rate of approximately 20 beats per minute.
b. Increase in contractility
c. Splanchnic/ renal vasoconstriction
d. Venoconstriction
Overall summary of effects of a change of posture
Cardiac Output:
• Increased SV and HR via increased sympathetic activity and decreased
parasympathetic activity.
• Starlings law- Increased venous return due to skeletal muscle pumps means that
preload is increased and therefore so is the stroke volume.
Negative effects:
• Reduced plasma volume opposes increased venous return.
○ Decreased plasma volume results from increased capillary pressure across
muscle walls
○ Loss of salt and water due to sweat.
Summary
• BP=CO X TPR
• In summary as the increase in cardiac output is greater than the decrease in TPR then
Blood Pressure will increase during exercise.
Stuart's Cardiovascular System Page 28
Haemostasis and thrombosis
15 February 2012
08:57
Learning Objectives
Describe in outline the normal haemostatic mechanisms including the
interaction of vessel wall, platelets, clotting factors and fibrinolytic
system
Describe in outline the normal haemostatic mechanisms including the
interaction of vessel wall, platelets, clotting factors and fibrinolytic system
Functions of haemostasis
1. Prevention of blood loss from intact vessels
2. Arrest of bleeding from injured vessels
Describe in outline how coagulation is regulated by the natural
anticoagulant pathways
Appreciate the principles of treatment of bleeding disorders and of
thrombosis
Describe in outline how coagulation is regulated by the natural
anticoagulant pathways
Fibrinolysis
• Plasminogen is a substrate for tissue plasminogen activator (tPA). Normally in the blood
they have low affinity for each other so new clots won't be constantly broken down.
• As fibrin is formed tPA and plasminogen can both bind to it and thus a reaction occurs
and plasmin is produced.
• Plasmin is a proficient proteolytic enzyme and causes production of Fibrin degredation
products.
• Streptokinase is a bacterial activator and thus a seeming analogue of tPA that is used
therapeutically for the thrombolysis of MI.
Haemostatic Plug Formation
1. Vessel constriction
2. Formation of an unstable platelet plug
○ Platelet adhesion
○ Platelet aggregation
3. Stabilisation of the plug with fibrin
○ Blood coagulation
4. Dissolution of clot and repair vessel
○ Fibrinolysis
XII
Blood coagulation
XIIa
XI
XIa
• Once a blood vessel is damaged the first molecule that is exposed is collagen.
• Platelets are either able to adhere directly to collagen or via Von Willebrand factor
"grabbing" them.
Platelet adhesion
IXa
IX
INTRINSIC
PATHWAY
X
Xa
Prothrombin
Coagulation proteinases
highlighted in red!
Va
Pl
Ca2+
or
platelet
GlpIb
GlpIa
collagen
Release of ADP
&
prostaglandins
Platelet aggregation
GlpIIb/IIIa
platelet
platelet
platelet
Fibrinogen
+
Ca2+
X
COMMON
PATHWAY
thrombin (IIa)
Fibrinogen
Fibrin
thrombin
XIIIa
XIII
Crosslinked fibrin
2. Indirect inhibition
○ Inhibition of thrombin generation by the protein C anticoagulant pathway
Factor Vai
T
Factor VIIIai
TM
APC
PS
Activated
Protein C
+ Protein S
• In platelet aggregation the release of ADP and prostaglandins result in platelets
being brought together (aggregated) to form the unstable plug with the being linked
by Fibrinogen and Calcium.
• If thromboxane is released instead then Calcium is not present and thrombin comes
to aid coagulation activation.
• Platelet activation is the conversion from a passive to an interactive cell.
○ Activated platelets:
 Change shape
 Change membrane composition
 Present new or activated proteins on their surface e.g. GpIIB/IIIa
• The liver, endothelial cells and megakaryocytes are sites of synthesis of clotting
factors.
Blood coagulation cascade
(ii) the protein C pathway down-regulates
thrombin generation
Thrombin
Endothelial
cells
Von
Willebrand
factor
EXTRINSIC
PATHWAY
VIIa
Ca2+
VIIIa
Pl
Ca 2+
platelet
Tissue factor
(vessel damage)
VIIa
Ca2+
Secondary Haemostasis
Platelet adhesion
• We have a potent anti-coagulant system that keeps us from forming clots all over our
body once all the enzymes are released in the clotting cascade.
1. Direct Inhibition
○ Antithrombin which is an inhibitor of thrombin and other clotting proteinases
○ Inhibits IXa, Xa, XIa (9,10,11) and thrombin (IIa).
○ Heparin accelerates the action of antithrombin and is found within mast cells and is
used in immediate anticoagulation in venous thrombosis and pulmonary
embolism.
Primary Haemostasis
Coagulation
activation
• Ultimate aim of the process is to produce thrombin so that fibrin can be produced.
• Tissue factor is a receptor for clotting factor VII, enzyme-substrate complex is VIIa.
• A zymogen is an enzyme that has not yet been activated which are converted to
proteinases, cofactors which need to be activated at surfaces.
• The surface is made of activated platelets (Pl) which localise and accelerate the
reactions.
• Contact activation- clotting in absence of tissue factor. Factor XII isn't extremely
important for effective clotting.
• Pl is a platelet membrane phospholipid.
XII
Blood coagulation
XIIa
PC
T
XI
PC
Endothelium
XIa
IXa
IX
Thrombomodulin
•
•
•
•
The protein C pathway down-regulates thrombin generation.
Thrombomodulin is present on normal endothelium which modulates thrombin activity.
Binding to it doesn't allow it to act as a coagulant.
Also has effects on Protein C which when activated breaks down Factors V and VII in
combination with Protein S.
• 5% of Caucasians have a modified Factor 5 called- Factor Va Leiden- this is not as easily
Tissue factor
(vessel damage)
VIIa
Protein C
INTRINSIC
PATHWAY
EXTRINSIC
PATHWAY
VIIa
VIIIa
Pl
X
Xa
Va
Pl
Prothrombin
X
thrombin (IIa)
Stuart's Cardiovascular System Page 29
Fibrinogen
Fibrin
COMMON
PATHWAY
IXa
IX
INTRINSIC
PATHWAY
• Thrombomodulin is present on normal endothelium which modulates thrombin activity.
• Binding to it doesn't allow it to act as a coagulant.
• Also has effects on Protein C which when activated breaks down Factors V and VII in
combination with Protein S.
• 5% of Caucasians have a modified Factor 5 called- Factor Va Leiden- this is not as easily
broken down so at more risk of thrombosis.
X
1.
2.
3.
4.
Antithrombin deficiency
Protein C deficiency
Protein S deficiency
Factor Va Leiden
Xa
Va
Pl
Prothrombin
Appreciate the principles of treatment of bleeding disorders and of
thrombosis
EXTRINSIC
PATHWAY
VIIa
VIIIa
Pl
X
COMMON
PATHWAY
thrombin (IIa)
Fibrinogen
Fibrin
thrombin
XIIIa
XIII
Crosslinked fibrin
Memory tools
Do everything by height as if you were drawing it.
• There will be the normal side (main clotting factors) and the special side, ones that
interact in special places.
• Remember it is where they appear by height in the cascade.
Normal side
12
11
9
10
(2)
Stuart's Cardiovascular System Page 30
Special side
7
8
5
13
Haemostasis II
15 February 2012
09:19
Learning Objectives
Describe what is meant by abnormal bleeding
Describe what is meant by abnormal bleeding
•
•
•
•
Describe patterns of abnormal bleeding with examples
Describe the manifestations of venous thrombosis
List the main risk factors for venous thrombosis
'Spontaneously' can be into joints or muscle
Out of proportion to the trauma/injury
Unduly prolonged
Restarts after appearing to stop
12% of the population have 'easy bruising'
Give a rough estimate of its prevalence
Be acquainted with the principles of treatment of venous thrombosis
Describe patterns of abnormal bleeding with examples
• Epistaxis- nose bleed not stopped after 10 mins compression
• Cutaneous haemorrhage or bruising without apparent trauma
• Menorrhagia requiring treatment or leading to anaemia, not due to structural
lesion of the uterus.
• Prolonged bleeding from trivial wounds, or in oral cavity or recurring
spontaneously in 7 days after wound. Spontaneous GI bleeding leading to anaemia.
Describe patterns of abnormal bleeding with examples
Primary Haemostasis
Deficiency
Common Examples
Collagen-vessel wall
Steroid therapy, age and interestingly scurvy. YYYARGGHHH
Describe patterns of abnormal bleeding with examples
Von Willebrand factor Von Willebrand disease (genetic)
Platelets
Aspirin and other drugs. Thrombocytopenia (low platelets)
Secondary Haemostasis- Fibrin Mesh Formation
Deficiency or defect of Coagulation Factors (I-XIII)
Haemophilia: FVIII or FIX due to genetic defect.
Liver disease (acquired- most coagulation factors are made in the liver)
Drugs (warfarin-inhibits synthesis of Coagulation factors)
Dilution- given crystalloids. Giving red blood cells without plasma dilutes coagulation
factors and inhibits clotting.
• Consumption (DIC- Disseminated intravascular coagulation)
•
•
•
•
•
Pattern of bleeding with defect in primary haemostasis
• Immediate
• Menorrhagia
• Bleeding after trauma/surgery
• Easy bruising
• Petechiae- typical of thrombocytopenia. Looks like a thousand pin pricks on the legs.
Platelets are constantly busy blocking small holes in blood vessels so once platelets
drop we can bleed through them.
• Nose bleeds (>20mins)
• Gum bleeding
Excess Fibrinolysis
Causes
Examples
Excess fibrinolytics (plasmin, tPA)
Therapeutic administration
Some tumours
Deficient antifibrinolytic (antiplasmin) Antiplasmin deficiency (genetic)
Disseminated intravascular coagulation:
• Generalised activation of coagulation by tissue factor.
• Association with sepsis, major tissue damage + inflammation.
• Powerful inflammatory response causes monocytes to express Tissue Factor which
shouldn't happen. Tissue factor should be external to the circulation, the expression of
it inside the bloodstream causes mass coagulation.
• Consumes and depletes coagulation factors and platelets.
• Activation of fibrinolysis depletes fibrinogen.
Consequences
• Widespread bleeding from IV lines, bruising and internal.
• Deposition of fibrin in vessels causes organ failure,
•
•
•
•
•
•
Thrombosis
• Artery- Myocardial infarction, stroke, limb ischaemia.
• Vein- Pain and swelling
○ These both result from an obstructed flow of blood.
• Can cause an embolism.
• Venous emboli to lungs (pulmonary embolus)
• Arterial emboli usually from the heart, may cause stroke or limb ischaemia. Typically
with atrial fibrillation.
Patterns of bleeding in secondary haemostasis:
Often delayed
Deeper joints and muscles
Not from small cuts etc.
Nosebleeds rare
Bleeding after trauma/surgery
After intramuscular injections
Describe the manifestations of venous thrombosis
• After a pulmonary embolism one can have:
List the main risk factors for venous thrombosis
Death
VT mortality 5%
Recurrence
20% in first 2 years and 4% pa thereafter
Thrombophlebitic syndrome Severe TPS in 23% at 2 years (11% with stockings)
Thrombosis is Multi-Causal Arising from Interacting
Genetic and Acquired Risk Factors
Pulmonary hypertension
4% at 2 years
Give a rough estimate of its prevalence
Risk
Acquired risk
Cumulative risk
Thrombotic
threshold
Risk from “ageing”
Genetic risk 2
Genetic risk 1
Age
•
•
•
•
Overall 1 in 1000.
Incidence doubles with each decade.
PE is cause of 10% of hospital deaths.
Estimated 25k preventable deaths per annum
List the main risk factors for venous thrombosis
Increased risk of thrombosis- "thrombophilia"
• Clinical:
• Thrombosis at young age
• ‘idiopathic thrombosis’
• Multiple thromboses
• Thrombosis whilst anticoagulated
• Laboratory
• Identifiable cause of increased risk
○ AT deficiency, Factor V Leiden, global measures of coagulation activity.
Virchow's triad
Acquired risks for thrombosis:
• Numerous conditions will alter blood coagulation, vessel wall and/or flow to precipitate
Blood
Stuart's Cardiovascular System Page 31
Genetic risk 1
Age
• Identifiable cause of increased risk
○ AT deficiency, Factor V Leiden, global measures of coagulation activity.
Virchow's triad
Blood
• Deficiency of anticoagulant proteins
○ Antithrombin
○ Protein C
○ Protein S
• Excess of coagulation factors
○ Factor V Leiden- increased activity due to protein C resistance
○ Factor VIII
○ Factor II and others
○ Thrombocytosis (increased platelets)
Vessel wall
• Many proteins active in coagulation are expressed on the surface of endothelial cells
and their expression is altered in inflammation.
○ Thrombomodulin
○ Tissue factor
○ Tissue factor pathway
Flow
• Stasis increases the risk of venous thrombosis
○ Surgery
○ Fracture
○ Long haul flight
○ Bed Rest
Stuart's Cardiovascular System Page 32
Acquired risks for thrombosis:
• Numerous conditions will alter blood coagulation, vessel wall and/or flow to precipitate
thrombosis or make it more likely.
• Oral contraceptive pill
• Pregnancy
• Surgery
• Inflammatory response
• Malignancy
○ OPSIM
Be acquainted with the principles of treatment of venous thrombosis
• Treatment: to lyse clot
• e.g. tPA (high risk of bleeding)
• Treatment: to limit recurrence/extension
• Increase anticoagulant activity
○ e.g. heparin (immediate acting, parenteral)
• Lower procoagulant factors
○ e.g. warfarin (oral, slow acting for long term therapy)
• Prevention (NICE Guidelines 2010)
• Assess individual risk and circumstantial risk
• All patients admitted should have VTE risk assessment
• Give prophylactic antithrombotic therapy
○ (eg heparin for in-patients)
○ +/ TED stockings
Atherosclerosis I
24 September 2012
21:46
Learning Objectives
The pathology and natural time-course of atherosclerosis, including
the meaning of commonly used pathological terms.
The connection between cholesterol and the development of
atherosclerosis.
The contributions that vascular endothelial cells, macrophages and
vascular smooth muscle cells make to the development of lesions.
The pathology and natural time-course of atherosclerosis, including the
meaning of commonly used pathological terms.
• Atherosclerosis is one of the most common diseases in the UK and is responsible for the
majority of deaths from cardiovascular disease.
• Atherosclerosis is a disease of medium and large arteries. Although the clinical
manifestations usually do not appear until middle-old age, the disease has a long “lead in”,
with changes in arteries occurring from early life. There is therefore plenty of time for
prevention.
The association between atherosclerosis and non-laminar blood flow
at arterial branch-points and -curvatures.
The reasons for atherosclerotic plaque instability leading to acute
clinical events.
The link between the pathology of atherosclerosis and clinical
symptoms.
The connection between cholesterol and the development of atherosclerosis.
• The disease starts as a thickening on one side of the artery. This develops into an
atherosclerotic “plaque”, consisting of a necrotic core of dead tissue covered and separated
from the blood by a fibrous cap.
• Probably the first event in the development of atherosclerosis is trapping within the arterial
wall of low density lipoproteins (LDL) rich in cholesterol. This occurs through the binding of
LDL to proteoglycans in the arterial intima, such as biglycan and versican.
The contributions that vascular endothelial cells, macrophages and vascular
smooth muscle cells make to the development of lesions.
• Once trapped in the arterial wall, LDL becomes chemically denatured by reactive oxygen free
radicals and/or by tissue enzymes (such as phospholipases). This results the phagocytosis of
LDL by macrophages, via scavenger receptors such as Scavenger Receptor A and CD36.
Macrophages that have taken up an excess of lipid are known as “foam cells”.
• Release of inflammatory mediators by macrophages and other cells results in the activation of
vascular endothelial cells with expression of adhesion molecules and chemo-attractants for
monocytes (such as cytokines, chemokines and ox-phospholipids), recruitment of more
monocytes from the blood and their differentiation within the arterial wall into macrophages.
Hence the process is self-perpetuating.
• As part of the inflammatory process activated macrophages (foam cells) can release:
1. Free radicals
2. Proteases
3. VSMC growth factors
4. Angiogenic factors
5. Apoptosis
Summary
Main cellular players:
• Vascular Endothelial Cells
○ Barrier function
○ Leukocyte recruitment
• Platelets
○ Thrombus generation
○ Cytokine and growth factor release
• Monocyte-macrophages
○ Foam cell formation
○ Cytokine and growth factor release
○ Major source of free radicals
○ Metalloproteinases
• Vascular smooth muscle cells
○ Migration and proliferation
○ Collagen synthesis
○ Remodelling and fibrous cap formation
• T lymphocytes
Stuart's Cardiovascular System Page 33
The association between atherosclerosis and non-laminar blood flow at arterial
branch-points and -curvatures.
• The distribution of atherosclerotic lesions is not random, with branch points and curvatures
being “hot spots”. This is probably because of the non-laminar blood flow at these sites. There
is evidence that laminar blood flow suppresses inflammatory activation of endothelial cells,
whereas non-uniform blood flow at hot spots may enhance it.
• High velocity lamina flow in common carotid creates sheer force that protects against it.
• Complex flow and oscillations sets up inflammatory gene expression in endothelial cells.
• As the plaque grows it is invaded by small blood vessels that develop from the vasa vasorum in
the adventitia. These vessels tend to bleed, and thereby contribute to the growth of the
necrotic core through the supply of erythrocyte-derived cell membranes.
• The stability of an atherosclerotic plaque is related to the strength of the fibrous cap
separating the blood from the necrotic core. The fibrous cap consists largely of collagens
synthesized by vascular smooth muscle cells.
The reasons for atherosclerotic plaque instability leading to acute clinical events.
• Plaque erosion- Breakdown of endothelial lining of the lesion without full rupture of the
fibrous cap.
• Plaque rupture- Breakdown of the fibrous cap of tissue separating the plaque from the blood.
• Rupture of the plaque is probably usually caused by the activity of proteases expressed by
macrophages fragmenting the matrix of the fibrous cap, but can also be caused by intraplaque haemorrhage (see above).
○ Metalloproteinases
• Vascular smooth muscle cells
○ Migration and proliferation
○ Collagen synthesis
○ Remodelling and fibrous cap formation
• T lymphocytes
○ Macrophage activation
The link between the pathology of atherosclerosis and clinical symptoms.
• Chronic symptom (eg angina, intermittent claudication) are attributable to limitation of blood
flow through atherosclerotic narrowing (stenosis) of the arterial lumen.
Factors predisposing to instability:
1.
2.
3.
4.
5.
Large soft eccentric lipid-rich core
Thin fibrous plaque
Low collagen content
Infiltrate of activates mo-mos and T cells
Neovascularization
Acute Events
• The Glagov Phenomenon- describes the early expansion of blood vessels to account for
plaque
• When the vessel has intermediate or advanced lesions this is window of opportunity for
primary prevention i.e. adjustment of the person's life style and reducing exposure to risk
factors e.g. stopping smoking, reducing cholesterol etc.
• As soon as complications such as stenosis appear, it is the time for clinical intervention. This is
known as secondary prevention and may include catheter based interventions or
revascularisation surgery. If the patient's condition is particularly bad then treatment for heart
failure may be needed.
• Occlusive Thrombus
• Blood coagulation at the site of rupture may lead to an occlusive thrombus and cessation
of blood flow
• Embolism
• Dislodgement of solid material (e.g. platelet plug, thrombus, cholesterol-rich plaque
contents) into the arterial circulation leading to occlusion at distant sites.
• The consequences depend on the size of the embolus and the target (e.g. brain, eye,
bowel, limbs)
○ This links into the video that we saw.
Effects of arterial occlusion from thrombosis or embolism
• Transient occlusion- Short ischaemia from an occlusion spontaneously resolves
• e.g. in brain "Transient Ischaemic attack"
• e.g. in eye "amaurosis fugax"
• Infarction is the death of tissue due to unresolved ischaemia
• e.g. in heart Myocardial Infarction
• e.g. in brain Cerebrovascular accident (CVA or stroke)
Vasa Vasorum gives a back door for leukocyte recruitment:
• As the plaque grows it becomes ischaemic so that blood doesn't get into the centre of the
plaque.
• This stimulates VCAM-1 that stimulates more vessel growth which are weak and can
easily rupture.
Stuart's Cardiovascular System Page 34
Atherosclerosis + Endothelium
21 February 2012
15:00
Learning Objectives
The basic functions of endothelial cells
The importance of vascular endothelium for the health of blood vessels
The importance of vascular endothelium in Cardiovascular diseases,
including atherosclerosis
How the endothelium regulates leukocyte recruitment and inflammation
How the endothelium drives the formation of new vessels (angiogenesis)
The importance of angiogenesis in cardiovascular diseases
Important Characteristics of Vascular Endothelium
The basic functions of endothelial cells
• Extremely large number of factors that they help regulate including angiogenesis,
vascular tone and permeability.
• Surface area greater than 1000m2
• Acts as a vital barrier separating blood from tissues.
• Formed by a monolayer of endothelial cells, one cell deep (contact inhibition)
○ Due to changing blood pressures cells need to be able to adapt and potentially
move.
• Endothelial cells are very flat, about 1-2 microns thick and 10-20 microns in diameter.
• Heterogeneity of cells.
• In vivo, endothelial cells live a very long life and have a low proliferation rate (unless
angiogenesis is required)
• The contact between 2 cells is regulated by many proteins and regulated as if it was a
zipper. Contact inhibition- essential survival mechanisms.
The importance of vascular endothelium in Cardiovascular diseases,
including atherosclerosis
• There is an important balance between protective and potentially damaging
actions of the vascular endothelium.
Protective
• Anti-inflammatory
• Anti-thrombotic
• Anti-proliferative
How the endothelium regulates leukocyte recruitment and inflammation
• Integrins get activated and bind to the vascular endothelium and interact with
molecules such as Selectins, Icams and Becams.
Deleterious
• Pro-inflammatory
• Pro-thrombotic
• Pro-angiogenic
• The problem of atherosclerosis is that you have a number of activators:
a. Mechanical stress
b. Viruses
c. Smoking
d. Inflammation
e. High Blood Pressure
f. High Glucose
• This then results in the balance being shifted to the pro-inflammatory side which
makes atherosclerosis worse.
How the endothelium drives the formation of new vessels (angiogenesis)
• Angiogenesis- Formation of new blood vessels by sprouting from pre-existing
blood vessels
• Leukocytes also engage with molecules such as ICAM and PECAM which allows
them to pass through the junctions between cells to enter the tissue.
Venules vs. arteries
• Tumours are vary good at producing angiogenic factor.
The importance of angiogenesis in cardiovascular diseases
Angiogenesis and cardiovascular disease
Stuart's Cardiovascular System Page 35
The importance of angiogenesis in cardiovascular diseases
Angiogenesis and cardiovascular disease
• Angiogenesis promotes plaque growth
• Therapeutic angiogenesis prevents damage in post-ischaemic tissue. Introduction
of growth factors/ stem cells may allow a new blood vessel to form and thus be a
natural bypass mechanism.
• Capillary: endothelial cells surrounded by
• Artery: Three thick layers, rich
basement membrane and pericapillary cells
in cells and extracellular matrix
(pericytes)
• Post-capillary venule: Structure similar
to capillaries but more pericytes
•
• Leukocytes cannot pass all the way through the blood vessels and gets stuck in the
sub- endothelial space.
Endothelial dysfunction in atherosclerosis
Leukocytes Recruitment
• Recruitment of leukocytes into tissues takes place normally during inflammation:
leukocytes adhere to the endothelium of post-capillary venules and transmigrate
into tissues.
• In atherosclerosis, leukocytes adhere to activated endothelium of large arteries and
get stuck in the subendothelial space.
• Newly formed post-capillary venules at the base of developing lesions provide a
further portal for leukocyte entry.
Endothelial dysfunction in atherosclerosis
Cellular Senescence
• Replication senescence: the limited proliferative capacity of human cells in culture
• Senescence as response to stress and damage: locks cells in a permanent form of
growth arrest.
• Linked to progressive shortening and dysfunction of telomeres (ends of chromosomes)
• Senescent cells have distinctive morphology and acquire specific markers, e.g. Beta gal.
• Senescence cells are pro atherosclerotic and therefore not good news.
• Endothelial cell senescence can be induced by CV risk factors, such as oxidative stress,
that promote increased cell replication to replace dead or damaged cells.
• These changes result in pro-inflammatory, pro-atherosclerotic and prothrombotic
phenotype.
The French Paradox
• Huge difference in male death rates in CAD in England compared to France.
• Resveratrol promotes endothelial protective pathways.
• Resveratrol acts as an anti-ageing compound and reduces vascular cell senescence.
Vascular permeability
• The endothelium regulates the flux of fluids and molecules from blood to tissues
and vice versa.
• Increased permeability results in leakage of plasma proteins through the junctions
into subendothelial space.
• In atherosclerosis there are a number of factors that contribute to occluding the
vessel. The include:
a. Smooth muscle migration
b. Foam-cell formation
c. T-cell activation
d. Adherence and aggregation of platelets
e. Adherence and entry of leukocytes.
Stuart's Cardiovascular System Page 36
Endothelial Progenitor Cells
• Circulating bone marrow derived CD34+ stem cells, of haematopoietic lineage which can
differentiate into mature endothelial cells.
• EPC mobilisation from the BM may be triggered by ischaemia, pro-angiogenic growth
factors, statins.
• Circulating EPC migrate and home to sites of ischaemia and contribute to re endotheliazation and angiogenesis
Pathophysiology of Heart Failure
24 February 2012
14:00
Learning Objectives
Epidemiology of heart failure
Heart Failure-Syndrome which arises when the heart is unable to maintain an appropriate blood
pressure without support.
Epidemiology of heart failure
Signs and symptoms of heart failure
• A clinical syndrome caused by an abnormality of the heart with characteristic pattern of
haemodynamic, renal, neural and hormonal responses.
Assess the severity of symptoms
Epidemiology of heart failure
Determine the aetiology of heart failure
Identify the concomitant diseases relevant to heart failure
Anticipate complications
Choose appropriate treatment
•
•
•
•
•
•
Prevalence- 1-3% in the population- 10% in those aged over 75.
Incidence= 0.5-1.5% per annum
Prognosis worse than cancer 50% dead in 3 years.
In community the mean age is 76 years old. Men:Women is 50:50
5% of acute hospital admissions and 10% bed occupancy
40% of admissions dead in one year.
Signs and symptoms of heart failure
Monitor progress and tailor treatment
Assess the severity of symptoms
NYHA classification of functional capacity
Class I- Patients with cardiac disease but without resulting limitation of physical
activity. Ordinary physical activity does not cause undue fatigue, palpitation, dyspnea, or
anginal pain.
Class II- Patients with cardiac disease resulting in slight limitation of physical
activity. They are comfortable at rest. Ordinary physical activity results in
fatigue, palpitation, dyspnea, or anginal pain.
Class III - Patients with cardiac disease resulting in marked limitation of physical
activity. They are comfortable at rest. Less than ordinary activity causes
fatigue, palpitation, dyspnea, or anginal pain.
Class IV - Patients with cardiac disease resulting in inability to carry on any physical
activity without discomfort. Symptoms of heart failure or the anginal
syndrome any be present even at rest. If any physical activity is
undertaken, discomfort is increased.
Progression of heart failure
Loss of myocardium
Fall of BP - baroreceptors ergoreflexes
& chemoreflexes activated
Maintains hormone activation
Onset of
heart failure
Quality
of life
The Nature of Heart Failure:
Bacterial invasion
Immune & inflammatory response
Onset of cachexia
Hastens demise
Progression
Sudden
death
Coronary
events
•
•
•
•
•
•
Patient is breathless, tired and retains fluid
Heart is damaged
Heart less effective as a pump
Marked neurohormonal activation
Quality of life is poor
Life expectancy reduced
Mild
Moderate
Severe
Time
Signs:
1. Pitting oedema- Pressing on the limb causes the skin to pit and remain so for a time being.
2. Increased jugular venous pressure
3. Ascites
4. Dilated heart
Death
Syndromes of Heart Failure
• Acute heart failure= Pulmonary oedema
• Circulatory collapse- Cardiogenic "shock" (poor peripheral perfusion, oliguria, hypotension)
• Chronic heart failure- Untreated, congestive undulating, treated, compensated
Determine the aetiology of heart failure
1. Arrhythmias
2. Valve disease- mitric regurgitation
3. Pericardial disease- pericardium is too tight so heart cannot expand and contract
effectively. TB- pericardial infection and fibrosis
4. Congenital heart disease- Fallous tetphalgy
5. Myocardial disease- death of heart muscle
○ Coronary artery disease
○ Cardiomyopathy- Dilated (DCM)- specific or idiopathic (IDCM). Hypertrophic (HCM or
HOCM or ASH). Restrictive. Arrhythmic right ventricular cardiomyopathy (ARVC)
○ Hypertension
○ Drugs:
 Beta blockers
 Calcium antagonists
 Anti-arrhythmics
○ Other or unknown
Dilated heart - no fluid retention in lungs
Trachea
Superior
vena cava
Bronchial bifurcation
Anterior rib
Vascular hilum
Spinal process
Clavicle
Scapula
Aortic arch
Left bronchus
Pulmonary artery
Left atrial appendage
Posterior rib
Heart disease and heart failure
Stuart's Cardiovascular System Page 37
Descending aorta
Right atrium
Diaphragm
Breast soft tissue
Superior
vena cava
Scapula
Aortic arch
Bronchial bifurcation
Anterior rib
 Calcium antagonists
 Anti-arrhythmics
○ Other or unknown
Left bronchus
Pulmonary artery
Left atrial appendage
Vascular hilum
Posterior rib
Descending aorta
Heart disease and heart failure
• Coronary heart disease is the leading cause of death in Europe
○ Left anterior descending coronary artery termed the widow maker.
○ Echocardiogram very common and well used to diagnose cardiac failure. Ventricular
wall should be 4.5 cm in diameter.
• Modern treatment increases survival
• Survivors are left with a damaged heart
• 50% of all survivors develop heart failure
• Deaths due to heart attacks are declining but due to heart failure are increasing
• the population is ageing and heart failure is commoner in old age
• Only a minority of patients with heart failure are receiving the latest drugs.
Right atrium
Breast soft tissue
Diaphragm
Liver
Gastric air bubble
Anticipate complications
Causes of death in heart failure
Identify the concomitant diseases relevant to heart failure
Cardiomyopathy and chronic heart failure
• Cardiomyopathy is heart disease in the absence of a known cause and particularly
coronary artery disease, valve disease and hypertension.
• Cause of approximately 5% of heart failure in a population
○
○
○
○
Hypertrophic cardiomyopathy
Dilated cardiomyopathy
Restrictive cardiomyopathy
Arrhythmic right ventricular
cardiomyopathy
1:500
1:5,000
1:10,000
1:5,000
1. Progression of heart failure
○ Increased myocardial wall stress
○ Increased retention of sodium and water
2. Sudden death
○ Opportunistic arrhythmia
○ Acute coronary event (often undiagnosed)
3. Cardiac event e.g. MI
4. Other cardiovascular event e.g. stroke, PVD
5. Non cardiovascular cause
○ PSCON
Hormonal mediators in heart failure
○ Mutation in Titan gene accounts for about a quarter of cardiomyopathy.
Causes of dilated cardiomyopathy
1.
2.
3.
4.
5.
6.
Infectious causes:
Viruses and HIV
Rickettsia
Bacteria
Mycobacteria
Fungus
Parasites
Dilators
Growth Factors
Noradrenaline
ANP
Insulin
Renin/angiotensin II Prostaglandin E2 and metabolites TNF alpha
Toxins and poisons
1.
2.
3.
4.
Constrictors
Ethanol
Cocaine
Metals
Carbon dioxide or hypoxia
Endothelin
EDRF
Somatostatin
Vasopressin
Dopamine
Angiotensin II
NPY
CGRP
Catecholamine
NO
Cytokines and oxygen radicals
Inflammatory markers and cytokines
Drugs- Chemotherapeutic agents, antiviral agents
Metabolic disorders- Nutritional deficiencies and endocrine disease
Collagen disorders, autoimmune cardiomyopathies, peri-partum cardiomyopathy,
neuromuscular disorders.
Inflammatory markers and cytokines
Causes of restrictive cardiomyopathy
Associated with fibrosis- Diastolic dysfunction: Elderly, hypertrophy, ischaemia, scleroderma
Infiltrative disorders- Amyloidosis, sarcoid disease, inborn errors of metabolism, neoplasia
Storage disorders- Haemochromatosis and haemosiderosis. Fabry disease, glycogen storage
disease
Endomyocardial disorders- Endomyocardial fibrosis, hypereosinophilic syndrome carcinoid,
metastases, radiation damage.
Organ specific:
All cell types:
Heart
Troponin T
Troponin I
Interleukin-1b
Interleukin-6
Tissue necrosis factor 
Vessel wall
ICAM-1
VCAM-1
E-selectin
P-selectin
Macrophages
Choose appropriate treatment
Objectives of treatment in chronic heart failure
1. Prevention
○ Myocardial damage
 Occurrence
 Progression of damage
 Further damaging episodes
○ Reoccurrence
 Symptoms
 Fluid accumulation
 Hospitalisation
2. Relief of symptoms and signs
○ Eliminate oedema and fluid retention
○ Increase exercise capacity
○ Reduce fatigue and breathlessness
3. Prognosis
○ Reduce mortality
Options in the treatment of heart failure
Lipoprotein-associated
phospholipase A2
Secretory phospholipase A2
Adipose tissue
Liver
C-reactive protein
Fibrinogen
Serum amyloid A
Monitor progress and tailor treatment
Management algorithm for heart failure
1.
2.
3.
4.
5.
6.
7.
8.
Establish that patient has heart failure
Determine aetiology of heart failure- do BNB send for an echo cardiogram
Identify concomitant disease relevant to heart failure- coronary artery disease
Asses severity of symptoms
Predict prognosis
Anticipate complications- clots, arrhythmias,
Choose appropriate treatment- beta blockers, ACE inhibitors + physical devices.
Monitor progress and tailor treatment- impella pump? Heart failure
Choose appropriate treatment
K+ sparing,
1. Drugs Diuretics, Loop, thiazide,
metolazone, spironolactone or combination
ACE inhibitors, Beta-blockers, Digoxin, Aspirin, statins, anticoagulants, Angiotensin
II receptor inhibitors, nitrates, hydralazine, antiarrhythmics, IV inotropes
2. Surgery, CABG or valve surgery
3. Implantable cardioverter-defibrillator - ICD, pacing
4. Haemofiltration, peritoneal dialysis or haemodialysis
5. Aortic balloon pump, ventricular assist devices cardiomyoplasty, volume reduction,
transplantation
Stuart's Cardiovascular System Page 38
Severe heart failure- possible treatments
Intravenous drugs○ Diuretics or combination of diuretics
○ Nitrates
○ Positive inotropes - dopamine/dobutamine
Fluid control
○ Haemofiltration
○ Peritoneal dialysis or haemodialysis
Devices
○ ICD or pacing
○ Intraaortic balloon pump
Ventricular assist device, total artificial heart
○ Ventricular assist device, total artificial heart
Surgery
○
○
○
○
Stuart's Cardiovascular System Page 39
CABG for "hibernation"
Valve surgery
Cardiomyoplasty, volume reduction/restriction
Transplantation
Hypertension
24 February 2012
15:00
SLIDES ARE ANNOTATED!!!
Summary
• BP levels are continuously distributed in a population
Parameters of hypertension
• The definition of hypertension is arbitrary and is based on the balance of the risks of
elevated BP versus the risks of investigation and treatment
• 90-95% of cases of hypertension have no identifiable cause (primary or essential
hypertension).
• Secondary hypertension is rare, but important causes include renal disease, tumours
secreting aldosterone (Conn’s syndrome), and tumours secreting catecholamines
(pheochromocytoma)
• RAT- Renal, Aldosterone, Tumour secreting catecholamines.
• Established hypertension is due to elevated peripheral vascular resistance
• The increased peripheral resistance in hypertension is due to active vasoconstriction
and structural narrowing of small arteries and loss of capillaries (rarefaction)
% of screened population
• Increased BP is associated with increased risk of cardiovascular disease – (strokes,
myocardial infarction (heart attacks), heart failure and atheromatous disease)
20
15
Australia (1979)
Veterans Admin
(1967,’70)
Hamilton (1964)
10
• Hypertension is associated with left ventricular hypertrophy, increased wall thickness
in large arteries, remodelling in smaller arteries and rarefaction of the
microvasculature
• The cause of primary hypertension is unknown but the strongest evidence implicates
renal abnormalities and/or excessive activity of the sympathetic nervous system
MRC (1985)
Australia (1980,’81)
5
0
50 60 70 80 90 100 110 120 130
Diastolic BP (mmHg)
BP distribution is unimodal and any distinction between normal and abnormal is arbitrary.
Hypertension can be defined as the level of blood pressure above which investigation and
treatment do more good than harm.
Age and hypertension
• Almost half of the people who suffer the disability and life years lost are below the
hypertensive cut off point.
• Need to target both hypertensive individuals and target people as a population to
reduce to the left of cut off point.
Causes of hypertension
Identifiable causes – secondary <5%
e.g.
• Renal disease, including renal artery
stenosis,
• Tumours secreting aldosterone (Conn’s
syndrome)
• Tumours secreting catecholamines
(pheochromocytoma)
• Oral contraceptive pill
• Pre-eclampsia/pregnancy associated
hypertension
• Rare genetic causes (e.g. Liddle’s syndrome)
Genes and environment in aetiology of primary hypertension
Genetics:
• Monogenic (rare)
• Complex polygenic (common) <1mmHG effect.
•
•
•
•
•
•
Environment:
Dietary salt intake
Obesity/ overweight, lack of exercise
Alcohol
Pre-natal environment (~birthweight)
Pregnancy (pre-eclampsia)
Other dietary factors and environmental exposures.
Unidentifiable cause – primary or essential
(90-95% of cases)
Haemodynamics of hypertension
• Estimates suggest that the heritability of high blood pressure is around 30-50%. Classical
single gene (monogenic) causes of hypertension are very rare, and it is believed that
numerous genes each contributing only a small effect explain the heritable component
of high BP.
Genes and blood pressure
• Twin and other studies suggest 30-50% of variation in blood pressure is attributable to
genetic variation.
○ Liddle's syndrome- Mutation in amiloride-sensitive tubular epithelial Na channel
○ Apparent mineralocorticoid excess- Mutation in 11 beta-hydroxysteroid
dehydrogenase
• Complex polygenic causes
○ Multiple genes with small effects (positive and negative)
○ Interactions with sex, other genes, environment
Major risks attributable to elevated blood pressure
• Increased risk of
○ Coronary heart disease
○ Stroke
○ Peripheral vascular disease/atheromatous disease
 Hypertension is commonly associated with thickened walls of large arteries and
acceleration of atherosclerosis.
 Hypertension may cause arterial rupture or aneurysms. This can lead to
thrombosis and haemorrhage which in turn can cause strokes.
○ Heart failure
Atrial fibrillation
Stuart's Cardiovascular System Page 40
BP= CO x TPR
1.
2.
3.
4.
5.
Increased total peripheral resistance
Reduced arterial compliance (higher pulse pressure)
Normal cardiac output
Normal blood volume/extracellular volume
Central shift in blood volume
○ Secondary to reduced venous compliance
Causes of elevated PVR in hypertension
• Excessive active narrowing of arteries- most likely short term vasoconstriction
• Structural narrowing of arteries- growth and adaptive remodelling process
• Loss of capillaries- Rarefaction.
Candidates causes of primary hypertension
• Kidney
○ Key role in BP regulation (guyton)
○ Best evidence especially in relation to salt intake
• Sympathetic nervous system
○ Evidence linking high sympathetic activity to the development of hypertension
• Endocrine/paracrine factor
○ INCONSISTENT EVIDENCE
○ Atrial fibrillation
○ Dementia/cognitive impairment
○ Retinopathy:
Normal
Kidney as a cause of hypertension
Hypertensive
Grade III retinopathy
Silver wiring
(wall thickening)
Haemorrhages
(wall rupture)
AV nipping
(wall thickening)
Hard exudates
(plasma leaks)
• The kidney exerts a major influence on BP – Guton’s concept of ‘infinite gain’ of renal
sodium/water/BP regulation
• Impaired renal function or blood flow is the commonest 2º cause of hypertension (e.g. renal
parenchymal disease, renal artery stenosis)
• Most monogenic causes of hypertension affect renal Na+ excretion
• Salt intake is strongly linked with blood pressures of human populations. Populations with low
salt have low population blood pressures and no rise in BP with age.
• Animals with reduced renal Na+ handling (genetic or experimental) develop hypertension. Excess
salt intake in many animals results in elevated blood pressure
• In rats hypertension can be ‘transplanted’ with the kidney, there is similar, though incomplete
data, in man
Hypertension and the microvasculature:
The retina illustrates microvascular damage in hypertension. There is
thickening of the wall of small arteries, arteriolar narrowing, vasospasm,
impaired perfusion and increased leakage into the surrounding tissue
• Hypertrophy of the heart is likely to occur if the afterload (blood pressure) increases
People eligible for Medicare
Vital Statistics of the United States, NCHS
500
450
400
350
300
250
200
150
100
50
0
Stroke
CHD
CHF (per 100,000 pt years)
CVD deaths (per 100,000 Population)
Heart failure and CHF
3
2.5
Men
Women
Normal mesentery
Hypertensive
2
1.5
• As one can see above, hypertension is associated with a reduction in capillary density. This
may result in impaired perfusion and an increase in Peripheral Vascular Resistance.
• Furthermore an elevated capillary pressure can cause damage and leakage which may put
more strain on the lymphatic system and thus contribute to the development of oedema.
1
0.5
0
1994
1997
2000
2003
Hypertension and the kidneys:
The prevalence of heart failure (CHF) is increasing (in contrast to other CVD)
Hypertension increases the risk of CHF 2 -3 fold
Hypertension probably accounts for about 25% of all cases of CHF
Hypertension precedes CHF in 90% of cases
The majority of CHF in the elderly is attributable to hypertension
Hypertension & the kidney
Renal dysfunction is common in hypertension (e.g. increased
(micro)albumin excretion in urine).
Extreme (accelerated/malignant hypertension) is now rare but leads to
progressive renal failure
Stuart's Cardiovascular System Page 41
Coronary Heart Disease
29 February 2012
08:59
Learning Objectives
Appreciate the global and UK burden of coronary heart disease
Appreciate the different clinical presentations of coronary heart disease
Appreciate the global and UK burden of coronary heart disease
Define myocardial ischaemia and its pathophysiology
State the main cardiac factors which give rise to chest pain
State the main clinical investigations that help diagnose angina
State some of the drug treatments for angina
Define thrombus, embolus, infarction
Define Virchow's triad and compare/contrast the three elements
State which of the triad has the dominant influence in arterial
thrombosis
Explain why thrombi are clinically important
Describe the inciting events leading to infarction and the characteristics
of infarctions, including the differences between red and white
infarctions
Outline the sequence of events following infarction and the factors that
influence their development
Describe the pathogenesis and clinical consequences of deep vein
thrombosis and pulmonary embolism
Describe pathogenesis and clinical consequences of fat embolism, gas
embolism, and amniotic fluid embolism
Myocardial Infarction:
• Myocardial cell death arising from interrupted blood flow to the heart.
○ Coronary plaque rupture causes pro-thrombotic factors to be exposed.
Therefore a thrombus can form and occlude the vessel.
○ Coronary plaque erosion.
○ Coronary dissection.
• Mechanisms of myocardial cell death
○ Oncosis- Passive ischaemic cell death
○ Apoptosis
Universal definition of Acute MI:
• The term myocardial infarction should be used when there is evidence of
myocardial necrosis in a clinical setting consistent with myocardial ischaemia.
Under these conditions any of the following criteria meets the diagnosis for
myocardial infarction:
○ Detection of rise and or fall of cardiac biomarkers (preferably troponin) with at
least one value above the 99th percentile of the upper reference limit (URL)
together with evidence of myocardial ischaemia with at least one of the
following:
 Symptoms of ischaemia
 ECG changes indiciative of new ischaemia (new ST-T changes or new left
bundle branch block)
 Development of pathological Q waves in the ECG.
 Imaging evidence of new loss of viable myocardium or new regional wall
motion abnormality.
Acute Coronary Syndromes
Global Burden
• Cardiovascular disease accounts for 17m deaths per year.
• Leading cause of death in both developed and low/medium income countries.
• Leading cause of death in age <70y.
• Leading cause of death in women- risk factors were inappropriately recognized
thought it was something else.
UK Burden
• 88,000 deaths per year due to CHD.
• 18% of deaths in men and 10% deaths in women.
• Mortality rates have reduced by about 40% however we still lag behind rest of
Western Europe.
• Main risks are use of tobacco, low physical activity, harmful use of alcohol and an
unhealthy diet. These collectively result in hypertension, obesity, diabetes mellitus
and hyperlipidaemia which are responsible for ~80% of CHD.
Appreciate the different clinical presentations of coronary heart disease
Sudden cardiac death
o Acute coronary syndrome
• Acute myocardial infarction
• Unstable angina
o Stable angina pectoris
o Heart failure
o Arrhythmia
Stable Angina:
• 2million individuals who suffer from it.
• 45k admissions.
• Angioplasty treats the symptoms rather than the cause.
• 9-10 billion of healthcare money.
Define myocardial ischaemia and its pathophysiology
Mismatch between myocardial oxygen supply and demand.
• Primary reduction in blood flow.
• Inability to increase blood flow to match increased metabolic demand.
• Prearterioles change diameter so that blood flow and pressure is maintained in arterioles
themselves.
• Arterioles within the myocardium are responsible for changing coronary resistance in
response to myocardial oxygen demand.
• Greater than 70% diameter stenosis in the pre-arterioles to alter coronary flow.
• Greater than 50% diameter stenosis under situations of stress
State the main cardiac factors which give rise to chest pain
Angina Pectoris
• This is a clinical diagnosis identified by discomfort in the chest, jaw, shoulder, arms or
back.
• It is provoked by exertion or emotional stress and can be relieved by rest of s.I GTN in
<5min.
• 20-30% plaque erosion
• 70-80% plaque rupture.
Define Virchow's triad and compare/contrast the three elements
Virchow's triad- This consists of three important factors that contribute to
thrombosis.
• Abnormal vessel wall- Inflammation, atherosclerosis
• Abnormal blood flow- Turbulent flow at bifurcations and stenoses, stasis.
• Abnormal blood constituents- Hypercoagulability, abnormal platelet function,
altered fibrinolysis, metabolic, hormonal factors.
Specific causes of chest pain
• Stenosis of blood vessels causing ischaemia.
• Thrombus in vessels causing ischaemia.
• Myocardial Infarction which caused by severe ischaemia.
State the main clinical investigations that help diagnose angina
• Functional tests- Is there myocardial ischaemia
• Anatomical tests- Is there coronary narrowing.
Endothelial dysfunction is also common to all three.
State which of the triad has the dominant influence in arterial
thrombosis
• In arterial thrombosis the main factor is abnormal vessel wall resulting from
atherosclerosis.
Describe the inciting events leading to infarction and the
characteristics of infarctions, including the differences between red
and white infarctions
Red and White Thrombus/Infarct
White
Red
Stuart's Cardiovascular System Page 42
State some of the drug treatments for angina
Red and White Thrombus/Infarct
White
Red
Platelet rich
Fibrin rich, with erythrocytes
Common in arterial thrombosis (high
pressure/turbulent circulation
Common in venous or low pressure
situations (stasis)
Benefit from antiplatelet therapy
Benefit from anticoagulant or antifibrinolytic therapy.
State some of the drug treatments for angina
• Improve blood supply:
○ Revascularization (PCI, CABG)
○ Vasodilators
• Reduce myocardial oxygen demand
○ HR (beta blockers, Ca antagonists, If blockers)
○ Wall stress (ACE inhibitors, Ca antagonists)
○ Metabolic modifiers (Beta oxidation to Oxidative phosphorylation).
• Prevent atherosclerosis progression and risk of death/MI.
Manage Thrombotic Burden/ Risk
• Necrosis passes as a wave front from endocardium outwards.
• MI in absence of reperfusion has an infarct size of 70%.
• Reperfusion reduces infarct size by 40% but part of remaining 30% infarct is due
to lethal reperfusion injury and is therefore preventable.
• When combined with cardioprotection the lethal reperfusion injury is reduced
meaning that the infarct size is only 5%.
Outline the sequence of events following infarction and the factors
that influence their development
Mechanisms underlying LV remodelling
• Infarct thinning, elongation, expansion
• LV dilatation
• reduce wall tension
• maintains cardiac output
• Non-infarcted myocardium
• LVH + myofilament dysfunction
• Altered electromechanical coupling
• Myocardial fibrosis
• Apoptosis
• Inflammation
Consequences of Adverse LV Remodelling
•
•
•
•
•
•
•
Increased systolic wall tension/stress
Increased MVO2
Reduced myocyte shortening
Increased diastolic wall tension/stress
Reduced subendocardial perfusion
Dysynchronous depolarization/contraction
Mitral regurgitation- valves aren't as effective thus some blood is able to leave
which causes other problems
• Ventricular arrhythmias
• Ventricular fibrillation
Describe pathogenesis and clinical consequences of fat embolism, gas embolism,
and amniotic fluid embolism
• Air embolism
○ Iatrogenic
○ Decompression sickness
○ Trauma
• Fat embolism
○ Trauma
• Amniotic fluid embolism
○ Pulmonary vascoconstriction, inflammation
○ ~1:54,000 deliveries, CFR 13-30%
○ Sudden CV collapse: Pulmonary HTN + RV failure -> LV failure
○ DIC
○ Rx: pulmonary vasodilators, FVIIa, ITU support
• Cholesterol embolism
○ Showers of microemboli from within plaque of large calibre artery
Stuart's Cardiovascular System Page 43
Describe the pathogenesis and clinical consequences of deep vein thrombosis
and pulmonary embolism
Embolism- An obstruction in a blood vessel due to a thrombus or other foreign matter that
gets stuck while travelling through the bloodstream.
• Arterial (ACS, TIA, stroke), air, fat, amniotic, foreign body/ material.
• Venous (thrombus- DVT, PE)
○ Sudden CV collapse: Pulmonary HTN + RV failure -> LV failure
○ DIC
○ Rx: pulmonary vasodilators, FVIIa, ITU support
• Cholesterol embolism
○ Showers of microemboli from within plaque of large calibre artery
○ Plaque rupture (spontaneous, traumatic, iatrogenic)
○ Embolization of plaque debris (cholesterol crystals, platelets, fibrin)
○ Lodging of emboli in arterioles 100-200μm diam.
○ Foreign body inflammatory response
○ End-organ damage due to microvascular plugging and inflammation
Stuart's Cardiovascular System Page 44
• Stasis of blood flow.
• POST DVT syndrome- venous ulceration, risk of infective ulcers around the limbs. Low
molecular weight heparins.
Integration of Responses to Haemorrhage
26 September 2012
22:22
Tutorial Scenario
Central venous
pressure low
Less blood returning to
heart – lower venous
return
Indicates low
blood volume
On admission 48 hrs later
Pulse (beats/min)
120
75
BP (mmHg)
85/50
120/80
Central venous pressure (cm saline) -7
5
Haemoglobin (g/l)
130
83
Urea (mM/l)
5
12
Blood pressure
Baroreceptor firing
• Male with partially severed femoral artery.
• On admission he was
○ Pale
○ Agitated
○ Thirsty
○ Cold extremities
Stroke volume
Cardiac output
Parasymp.
to heart
Symp. to
heart
Mean BP = CO x TPR
CO = HR x SV
Symp. tone
to blood
vessels
HR
Force of
contraction
TPR
Heart Rate
Redistribution of blood flow – sympathetic
vasoconstriction is not uniform
• Increasing sympathetic action of the heart increases the heart rate by raising the gradient of
the pre-potential of sino-atrial nodal cells, because they can achieve excitation quicker heart
rate will be increased.
Subject is pale and
skin feels cold
Blood flow to skin
Blood flow to skeletal muscles
Cerebral and cardiac blood
flow unchanged
Blood flow to gut
Blood flow to kidney
Angiotensinogen (liver)
Low renal artery pressure
renin
AI
ACE
Aldosterone (adrenal cortex)
Na retention
AII
Vasoconstrictor
Thirst
Contractility
• Below is a schematic diagram of a nephron of the kidney. Note that the macula densa
cells detect the decreased sodium levels which causes the juxtaglomerular cells to
produce renin.
• An increase in force of contraction is mediated by raised levels of cyclic AMP. Cyclic AMP
helps to activate Protein Kinase A which synthesises and up regulates proteins needed for
calcium entry and release within the cell.
Total Peripheral Resistance
• Both alpha and adrenoreceptors can have effects on the tone of the vascular smooth
muscle.
• In smooth muscles Calcium and Calmodulin complex activates Myosin light chain kinase.
Low venous return
Vessel damage
Stuart's Cardiovascular
System Page 45
Haemostatic
mechanisms
Left atrial pressure
ADH secretion (post. pit)
Low venous return
Left atrial pressure
Vessel damage
ADH secretion (post. pit)
Haemostatic mechanisms
Kidney tubule permeability to water
Preserve blood volume
H2O reabsorption
Volume
replacement
Low urine output
Na retention
Process of smooth muscle contraction via Myosin Light Chain Kinase:
1. Calcium ions either released from the sarcoplasmic reticulum via ryanodine receptors, or
from the extracellular space bind to calmodulin.
2. This binding results in the activation of MLCK which phosphorylates the light chain of
myosin at serine residue 19.
3. This phosphorylation enables a myosin and actin crossbridge to form and thus contraction
to begin.
• This pathway is particularly important because within smooth muscle fibres there is no
troponin and thus this is the main mechanism of regulating contraction.
• As we can see above the inositol triphosphate (IP3) that is expressed as a result of alpha
adrenoreceptor activity will aid smooth muscle contraction and thus cause
vasoconstriction. This is important in maintaining blood pressure.
• Likewise the cAMP from B2- adrenoreceptors inhibits this process and will cause
vasodilation. This is used to increase the blood flow to muscles during a sympathetic
discharge.
Lumen Size and Mechanics
Volume Replacement
• Crystalloid Solutions
○ Isotonic (0.9%) sodium chloride solution
○ Ringer's lactate
• Colloids (Haemacel, Gelofusion)
○ These colloids have a high plasma oncotic pressure thus fluid isn't lost into ECF.
• Blood products (if no response after infusion of 2 litres of crystalloid)
○ Packed red blood cells
○ Fresh Frozen Plasma (FFP)
○ Whole blood crossmatched
Respiratory System
• Chemoreceptors are chemosensitive cells sensitive to oxygen lack, CO 2 excess, or H+ ion
excess.
• Chemoreceptors are located in carotid bodies near the carotid bifurcation and on the arch
of the aorta.
• Activation of chemosensitive receptors results in excitation of the vasomotor centre.
• Low levels of oxygen, high levels of CO2 and a drop in pH (increase in H+) results in the
chemoreceptors firing and exciting the vasomotor centre. This then causes an increase in
sympathetic activity and a raise in blood pressure.
• Thus there are cardiovascular changes in response to respiratory needs.
• As resistance is inversely proportional to the radius to the power of four, a small change in
radius will result in a large change in resistance.
• Since flow is the change in pressure divided by the resistance, the small change in pressure
will have a large direct on the flow of blood passing through a vessel.
Integration with other Systems
Integration with other systems
Physiological challenge
renal response
CVS response
respiratory response
Integrated response
fluid, O2 and CO2 delivery
and exchange
Preservation of the internal environment
SUCK ON THAT CVS!!!! 21st lecture boomed out
Stuart's Cardiovascular System Page 46